Hypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of ...1,25-dihydroxyvitamin D 1,25(OH)2D, and impaired degradation of 1,25(OH)2D. The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D 25(OH)D that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)2D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)2D is impaired as a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)2D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)2D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)2D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.
Abstract The presentation of hypophosphatasia (HPP) diagnosed in adults demonstrates a wide range of clinical manifestations, many of which are nonspecific. We sought to assess clinical ...characteristics of adult HPP by evaluation of Mayo Clinic Rochester adults diagnosed with HPP from 1976 through 2008. Subjects were identified by diagnostic code or medical records. Inclusion criteria were age ≥ 18 years at diagnosis; low serum alkaline phosphatase (AP) without bisphosphonate therapy; and one additional element: elevated pyridoxal 5′-phosphate (PLP) or urine phosphoethanolamine (PEA), evidence of osteomalacia, or family history. We were unable to distinguish manifesting carriers from silent unaffected carriers due to lack of a prospective standardized clinical evaluation and the absence of genetic testing. HPP was diagnosed in 22 unrelated adults (median age 49 years; 68% women). Most patients (68%) were symptomatic at presentation with features including musculoskeletal pain (41%) or incident fracture (18%). A history of fracture was present in 54%: hip/femoral neck (23%), feet (23%, all women), wrist (18%), and spine (9%, all men). Nine patients (36%) had multiple fractures while 4 (all women) had subtrochanteric femur fractures. Radiographic chondrocalcinosis (27%) and documented pyrophosphate arthropathy (14%) were only observed in women. Median minimum serum AP was 43% below the lower normal limit. Urine PEA was elevated in 15/16 patients (94%). PLP median was 68 μg/L (normal, 5–50 μg/L) and all (n = 8) were above normal. Symptomatic subjects had more fractures and chondrocalcinosis, lower median minimum AP and PLP and higher median PEA levels. Clinical features more common in fracture patients included symptoms at presentation, history of childhood rickets, dental abnormalities, lower median minimum AP and PLP, and higher median urine PEA. Four subjects had iliac crest bone biopsies, with 2/4 specimens consistent with osteomalacia. These results suggest that adult HPP demonstrates a wide spectrum of clinical manifestations including musculoskeletal pain, fractures, chondrocalcinosis and dental anomalies with some overlap in laboratory characteristics in relationship to disease severity. In addition to genetic and environmental factors, gender may influence the clinical expression of HPP.
Abstract As female athletic participation has increased, the positive effects of exercise on health have become evident. However, with this growth in sports activity, a set of health problems unique ...to the female athlete has emerged. The female athlete triad as first described in 1992 by the American College of Sports Medicine consisted of disordered eating, amenorrhea, and osteoporosis; the definition was updated in 2007 to include a spectrum of dysfunction related to energy availability, menstrual function, and bone mineral density. For this review, a comprehensive search of databases—MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Scopus, from earliest inclusive dates to January 2013—was conducted by an experienced librarian with input from the authors. Controlled vocabulary supplemented with keywords such as female athlete triad, amenorrhea, oligomenorrhea, fracture, osteopenia, osteoporosis, bone disease, anorexia, bulimia, disordered eating, low energy availability was used to search for articles on female athlete triad. Articles addressing the prevalence, screening, and management of the female athlete triad were selected for inclusion in the review. This article reviews the current definitions of the triad components, epidemiology, pathophysiology, and recommended screening and management guidelines. The lack of efficacy of current screening of athletes is highlighted. Low energy availablity, from either dietary restriction or increased expenditure, plays a pivotal role in development of the triad. Athletes involved in “lean sports” (those that emphasize weight categories or aesthetics, such as ballet, gymnastics, or endurance running) are at highest risk. Treatment is centered on restoring energy availability to reverse adverse changes in the metabolic milieu. Prevention and early recognition of triad disorders are crucial to ensure timely intervention. Caregivers and physicians of female athletes must remain vigilant in education, recognition, and treatment of athletes at risk.
Abstract Objective To determine temporal trends in incidence and risk factors of nutritional rickets in a community-based population. Patients and Methods Rochester Epidemiology Project data were ...used to identify all children (aged <18 years) residing in Olmsted County, Minnesota, between January 1, 1970, and December 31, 2009, with diagnostic codes corresponding to rickets, vitamin D deficiency, hypovitaminosis D, rachitis, osteomalacia, genu varum, genu valgum, craniotabes, hypocalcemia, hypocalcemic seizure, and tetany. Record abstraction was performed to select individuals with radiographic confirmation of rickets. Age- and sex-matched controls were identified for the evaluation of risk factors. The main outcome measure was radiographic evidence of rickets without identifiable inherited, genetic, or nonnutritional causes. Incidence rates were calculated using Rochester Epidemiology Project census data. Results Of 768 children with eligible diagnostic codes, 23 had radiographic evidence of rickets; of these, 17 children had nutritional rickets. All 17 children were younger than 3 years, and 13 (76%) were of nonwhite race/ethnicity. Clinical presentation included poor growth (n=12), leg deformity (n=8), motor delay (n=5), leg pain (n=3), weakness (n=3), and hypocalcemia or tetany (n=2). The incidence of nutritional rickets in children younger than 3 years was 0, 2.2, 3.7, and 24.1 per 100,000 for the decades beginning in 1970, 1980, 1990, and 2000, respectively ( P =.003 for incidence trend). Nutritional rickets was associated with black race, breast-feeding, low birth weight, and stunted growth ( P <.05 for all). Four of 13 patients (31%) who underwent 25-hydroxyvitamin D testing had values less than 10 ng/mL. Conclusion Nutritional rickets remains rare, but its incidence has dramatically increased since 2000. Not all cases of rickets can be attributed to vitamin D deficiency.
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.
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.
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
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.
Background:
Mutations of the CYP24A1 gene, which encodes the 1,25-dihydroxyvitamin D-24-hydroxylase cytochrome P450, Cyp24A1, are predicted to result in elevated 1,25-dihydroxyvitamin D ...concentrations, hypercalcemia, hypercalciuria, nephrolithiasis, and bone disease. Treatment of hypercalcemia associated with CYP24A1 gene mutations has not been described.
Methods:
The genetic basis of a syndrome in a 44-yr-old Caucasian male characterized by intermittent hypercalcemia, hypercalciuria, elevated serum 1,25-dihydroxyvitamin D, undetectable serum 24,25-dihydroxyvitamin D, metabolically active nephrolithiasis, and reduced bone mineral density of the lumbar spine was examined. Sequencing of the CYP24A1 gene and biochemical and genetic analysis of seven family members in three generations was carried out. Because of hypercalcemia, hypercalciuria, and metabolically active nephrolithiasis, the patient was treated with a cytochrome 3A inhibitor, ketoconazole, 200 mg orally every 8 h, for 2 months.
Results:
The sequence of the CYP24A1 gene showed two canonical splice junction mutations in the proband. Analysis of family members showed a phenotype associated one or both mutations, suggesting autosomal dominant transmission with partial penetrance of the trait. After therapy with ketoconazole, statistically significant reductions in previously elevated urinary calcium into the normal range were noted. Previously elevated serum 1,25-dihydroxyvitamin D and calcium concentrations decreased, and previously decreased PTH concentrations increased into the normal range, but the differences were not statistically significant.
Conclusions:
In a syndrome characterized by intermittent hypercalcemia, hypercalciuria, elevated 1,25-dihydroxyvitamin D, undetectable 24,25-dihydroxyvitamin D concentrations, splice junction mutations of the CYP24A1 gene, and autosomal dominant transmission of the trait, treatment with ketoconazole is useful in reducing urinary calcium.
The Rickets Severity Score (RSS) was used to evaluate X-linked hypophosphatemic rickets (XLH), a genetic disorder mediated by increased circulating FGF23. The reliability of the RSS was assessed ...using data from a randomized, phase 2 clinical trial that evaluated the effects of burosumab, a fully human anti-FGF23 monoclonal antibody, in 52 children with XLH ages 5 to 12 years. Bilateral knee and wrist radiographs were obtained at baseline, week 40, and week 64. We evaluated the relationships of the RSS to the Radiographic Global Impression of Change (RGI-C), serum alkaline phosphatase (ALP), height Z-score, 6-minute walk test (6MWT) percent predicted, and the Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI). The RSS showed moderate-to-substantial inter-rater reliability (weighted kappa, 0.45–0.65; Pearson correlation coefficient (r), 0.83–0.89) and substantial intra-rater reliability (weighted Kappa, 0.66; r = 0.91). Baseline RSS correlated with serum ALP (r = 0.47). Baseline RSS identified two subgroups (higher RSS ≥1.5 and lower RSS RSS <1.5) that discriminated between subjects with greater and lesser rachitic disease. Higher RSS was associated with more severe clinical features, including impaired growth (Z-score, −2.12 vs −1.44) and walking ability (6MWT percent predicted, 77% vs 86%), more severe self-reported pain (29.9 more severe vs 45.3 less severe) and less physical function (29.6 more severe vs 40.9 less severe). During burosumab treatment, greater reductions in RSS corresponded to higher RGI-C global scores (r = −0.65). Improvements in RSS correlated with decreased serum ALP (r = 0.47). These results show the reliability of the RSS in XLH, and demonstrate that higher RSS values are associated with greater biochemical, clinical, and functional impairments in children with XLH.
•Rickets Severity Score (RSS) is a quantitative measure of radiographic severity.•Greater RSS severity is associated with worse clinical presentation at baseline.•The RSS had substantial inter- and intra-rater agreement.•The RSS permits masking and adequate statistical power for small sample sizes.•RSS is a reliable and valid method for assessing rickets severity in XLH.
Primary Hyperparathyroidism (PHPT) is rare in pediatric patients. Data regarding surgical outcomes are scarce.
Single-center retrospective review (1994–2020) of patients ≤21 years undergoing surgery ...for PHPT.
66 patients were identified (61% female, 17 ± 3 years). 71% of patients were symptomatic at diagnosis. 32% of patients had known familial syndromes, most commonly MEN-1. 23% of patients without a known mutation had genetic testing, 22% positive. 56% of the total and 19% of the familial cohort underwent focused exploration. Single gland disease was found in 19% of familial vs 85% of sporadic cases, p < 0.00001. Persistence was 9%, all in the sporadic group, p = 0.11. Recurrence was 15%: 38% in the familial vs 2% in the sporadic groups, p=0.0004. Time to recurrence was 59 months (Q1-38, Q3-95), familial 61 vs 124 months sporadic, p=0.001.
Pediatric PHPT is frequently sporadic, although 5% of apparent sporadic cases are secondary to syndromes. Familial cases have higher rates of recurrence, requiring closer follow-up.
•Pediatric hyperparathyroidism is frequenyl sporadic.•5% of cases without family history ar attributed to genetic syndromes.•Sporadic HPT is due to single adenoma at a similar rate to sporadic adult population (85%).•Familila cases have higher recurrence rates with earlier onset, requiring close follow-up ad interventions are often needed.
Protein-truncating germline pathogenic variants in the N- and C-terminal exons (2, 9, and 10) of the MEN1 gene may be associated with aggressive pancreatic neuroendocrine tumors. However, the impact ...of these variants on parathyroid disease is poorly understood. We sought to investigate the effects of genotype and surgical approach on clinical phenotype and postoperative outcomes in patients with multiple endocrine neoplasia type 1 (MEN1)-related primary hyperparathyroidism.
We identified patients with MEN1 evaluated at our institution from 1985 to 2020 and stratified them by genotype, (truncating variants in exons 2, 9, or 10, or other variants), and index surgical approach, (less-than-subtotal parathyroidectomy <SPTX, SPTX, or total parathyroidectomy). We analyzed baseline characteristics, persistent/recurrent disease rates, and incidence of postoperative hypoparathyroidism.
Of the 209 patients we identified, primary hyperparathyroidism was diagnosed in 194 (93%) and at a younger median age in those with truncating exon 2, 9, or 10 variants compared with other variants (27 years vs 31 years; P = .006). Median disease-free survival was significantly worse in patients who underwent <SPTX (60 months) than those who underwent <SPTX (152 months; P = .0005) or total parathyroidectomy (210 months; P = .04). Patients with truncating exon 2, 9, or 10 variants who underwent <SPTX had significantly shorter median disease-free survival than those with other variants (30 vs 84 months; P = .007). Prolonged hypoparathyroidism rates after final surgery were highest after total parathyroidectomy (40%), followed by <SPTX (9%) and SPTX (7%).
The MEN1 genotype may affect the age of onset of primary hyperparathyroidism and the time to recurrence after surgery. <SPTX at index operation should be performed with caution, especially in patients with truncating MEN1 variants in exons 2, 9, or 10, as the higher risk of recurrence is not offset by a decreased incidence of permanent hypoparathyroidism compared to upfront SPTX.
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