Differentiating Familial Hypocalciuric Hypercalcemia From Primary Hyperparathyroidism

ObjectiveBecause the clinical features of familial hypocalciuric hypercalcemia (FHH) overlap significantly with those of primary hyperparathyroidism (PHPT), various means of differentiating between the two diseases have been suggested. Here we present a review of the clinical delineation of these two diseases.MethodsReview of the English language literature on FHH and PHPT.ResultsFHH is a rare genetic disorder generally resulting in asymptomatic hypercalcemia of minimal clinical consequence. It is easily misdiagnosed as PHPT because both entities can manifest as hypercalcemia with an inappropriately normal or elevated level of parathyroid hormone. The 2 disorders differ in renal processing of calcium, and a number of indices of renal calcium excretion have been proposed to differentiate the 2 entities. However, the two disorders have considerable overlaps in their ranges on these indices making differentiation a challenge. There are many mutations in the calcium-sensing receptor (CaSR) gene associated with FHH and it is becoming increasingly recognized that the CaSR has broad functional variability.ConclusionThe calcium:creatinine clearance ratio (CCCR) is the consensus biochemical test to differentiate between PHPT and FHH. However, this test is still limited by a considerable indeterminate range, and definitive diagnosis of FHH requires genetic testing. A combination of clinical suspicion, biochemical testing, and genetic analysis is required to differentiate PHPT from FHH and thus spare patients with FHH from nontherapeutic operative treatment. (Endocr Pract. 2013;19:697-702)     

A novel <Emphasis Type="Italic">CASR</Emphasis> mutation in a Tunisian FHH/NSHPT family associated with a mental retardation

The calcium-sensing receptor (CASR), a plasma membrane G-protein coupled receptor, is expressed in parathyroid gland and kidney, and controls systemic calcium homeostasis. Inactivating CASR mutations have previously been identified in patients with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). The aim of the present study is to determine the underlying molecular defect of FHH/NSHPT disease in a consanguineous Tunisian family. Mutation screening was carried out using RFLP-PCR and direct sequencing. We found that the proband is homozygous for a novel 15 bp deletion in the exon 7 (c.1952_1966del) confirming the diagnosis of NSHPT. All the FHH members were found to be heterozygous for the novel detected mutation. The mutation, p.S651_L655del, leads to the deletion of 5 codons in the second trans-membrane domain of the CASR which is thought to be involved in the processes of ligand-induced signaling. This alteration was associated with the evidence of mental retardation in the FHH carriers and appears to be a novel inactivating mutation in the CASR gene. Our findings provide additional support for the implication of CASR gene in the FHH/NSHPT pathogenesis.     

Low Urine Calcium Excretion in African American Patients with Primary Hyperparathyroidism

ObjectiveTo evaluate the prevalence of low urine calcium excretion in African American patients with primary hyperparathyroidism (PHPT), a common disorder associated with bone and renal complications, and to assess the distinction between PHPT and familial hypocalciuric hypercalcemia (FHH), a rare benign genetic disease.MethodsWe conducted a retrospective study on a cohort of 1,297 patients in whom a 24-hour urine study was performed for measurement of urine calcium and creatinine. PHPT was diagnosed if the serum calcium concentration was ≥ 10.5 mg/dL and intact parathyroid hormone (PTH) was ≥ 40 pg/mL. Patients receiving medications that affect urine calcium or with glomerular filtration rate ≤ 30 mL/min were excluded.ResultsNinety-six patients satisfied the diagnostic criteria for PHPT. The African American (n = 70) and non-African American (n = 26) patients did not differ in their mean age, body mass index, glomerular filtration rate, serum PTH, 25-hydroxyvitamin D levels, and 24-hour urine creatinine values. Median values of urine calcium/creatinine (mg/g) were 122 for African American versus 214 for non-African American patients (P = .006). Thirty-one of 70 African American patients (44%) had a urine calcium/creatinine ratio ≤ 100 mg/g, whereas only 2 of 26 non-African American patients (8%) had this value (P = .001).ConclusionThe prevalence of low urine calcium excretion among African American patients with PHPT is unexpectedly high. A threshold of 100 mg/g urine calcium/ creatinine identified 44% of such patients with PHPT as having FHH in this cohort. Therefore, other clinical criteria and laboratory variables should be used to distinguish PHPT from FHH in African American patients with PTH-dependent hypercalcemia. (Endocr Pract. 2011;17: 867-872)     

Familial Hyperparathyroidism Due to A Germline Mutation of the Cdc73 Gene: Implications for Management and Age-Appropriate Testing of Relatives At Risk

ObjectiveTo discuss the implications of a young age at diagnosis in a family member with hyperparathyroidismjaw tumor syndrome, the youngest published case to date, due to a mutation of the CDC73 gene (formerly known as HRPT2); to review this family with regard to modifications of guidelines for surveillance of hyperparathyroidism and other associated features in affected and at-risk relatives; and to discuss surgical recommendations in this syndrome.MethodsA review of English-language publications in PubMed and a review of GeneReviews were conducted pertaining to the subject of familial hyperparathyroidism. A case is described, and the family pedigree is discussed.ResultsReview of the literature revealed that CDC73-related disorder has not previously been reported in patients younger than 10 years. This finding has been the basis for the recommendation for initiation of surveillance for disease manifestations at that age. Review of the family history of our current patient revealed a 7-yearold nephew with hypercalcemia attributable to primary hyperparathyroidism.ConclusionSurveillance of hyperparathyroidism in affected persons and genetic testing of relatives at risk are currently recommended to start at 10 years of age. We recommend that these be conducted at a younger age, preferably 5 to 10 years before the earliest diagnosis of hyperparathyroidism within the family, and potentially at birth in families with a known mutation of the CDC73 gene, in light of the malignant potential of the disease. (Endocr Pract. 2011;17:602-609)     

Calcium-Creatinine Clearance Ratio is not Helpful in Differentiating Primary Hyperparathyroidism from Familial Hypercalcemic Hypocalciuria: A Study of 1,000 Patients

Objective: With increasing recognition of more subtle presentations of primary hyperparathyroidism (pHPT), laboratory values are frequently seen in a range that would be expected for patients who have familial hypercalcemic hypocalciuria (FHH). Calcium-creatinine clearance ratio (CCCR) has been advocated as a diagnostic tool to differentiate between these two disorders. However, it is limited by an indeterminate range (0.01 to 0.02). The aim of this study was to assess the relevance of CCCR in a modern series of patients with surgically managed pHPT.Methods: We performed a retrospective cohort study of 1,000 patients who underwent parathyroid surgery for pHPT over 11 years. CCCR was evaluated by degree of biochemical derangement, single versus multiple gland disease, and interfering medications.Results: Patient demographics and resected histopathology were typical for a current series of patients with pHPT. In retrospect, none of the patients were suspected to have FHH postoperatively. CCCR was <0.01 for 19.0%, between 0.01 and 0.02 for 43.7%, and >0.02 in 37.3%. Distribution of CCCR for patients free from interfering medications and different histologic subtypes were the same. One-third of the cohort had mild calcium elevations, more typical for FHH. Of these, almost two-thirds had a CCCR in a range suspect for FHH (<0.02).Conclusion: To our knowledge, this is the largest series to evaluate the validity of CCCR for patients with surgically confirmed pHPT. The utility of CCCR in screening for FHH is limited, as 63% of modern patients with confirmed pHPT have low values.Abbreviations: CaSR = calcium sensing receptor; CCCR = calcium-creatinine clearance ratio; CeE = calcium excretion; FHH = familial hypercalcemic hypocalciuria; pHPT = primary hyperparathyroidism; PTH = parathyroid hormone     

Identifying Parathyroid Hormone Disorders and their Phenotypes through a Bone Health Screening Panel: It's not Simple Vitamin D Deficiency!

Objectives: To determine the utility of bone health screening panels in identifying disorders of parathyroid gland secretions.Methods: A retrospective analysis of biochemical parameters in a bone health screening panel (BHSP) was conducted. Low and high cutoffs were applied to determine hypofunctioning and hyperfunctioning conditions related to parathyroid hormone. Clinical phenotypes of parathyroid gland abnormalities were determined using a combination of levels of calcium, 25-hydroxyvitamin D, and intact parathyroid hormone (iPTH). A PTH nomogram was applied to calculate the maximum expected PTH for existing levels of 25-hydroxyvitamin D. Medical records of patients were reviewed for clinical validation of biochemical findings.Results: Sixty-eight percent of subjects showed abnormal PTH secretion. Primary hyper- and hypoparathyroidism were detected in 1% (n = 5) and 0.4% (n = 2) of subjects, respectively. Normocalcemic hyperparathyroidism and hypercalcemia with inappropriately high-normal PTH were identified in 8.5% (n = 37) and 2% (n = 10) of subjects, respectively. All subjects with primary and normocalcemic hyperparathyroidism had higher measured PTH than calculated maximum PTH using the PTH nomogram. Secondary hyperparathyroidism and functional hypoparathyroidism were present in 18% (n = 88) and 39% (n = 194) of subjects, respectively. High prevalence of bone pains, renal stones, and low bone mineral density were identified in patients with abnormal PTH secretion.Conclusion: Panel testing is useful in early diagnosis of metabolic bone disorders related to PTH. A BHSP helps identify normocalcemic hyperparathyroidism and hypercalcemia with inappropriately high PTH.Abbreviations:25OHD = 25-hydroxyvitamin DAKUH = Aga Khan University HospitalBHSP = bone health screening paneliPTH = intact parathyroid hormonemaxPTH = maximum parathyroid hormoneMBD = metabolic bone diseaseNCHPT = normocalcemic hyperparathyroidismPHPT = primary hyperparathyroidismPTH = parathyroid hormoneSHPT = secondary hyperparathyroidismVDD = vitamin D deficiency     

Suppressibility of Parathyroid Hormone in Primary Hyperparathyroidism

ObjectiveTo describe an unusual case of pathologically confirmed primary hyperparathyroidism in a patient presenting with severe hypercalcemia and an undetectable parathyroid hormone (PTH) level.MethodsWe present a detailed case report and outline the serial laboratory findings. In addition, the possible causes of low serum PTH levels in the setting of primary hyperparathyroidism are discussed.ResultsA 16-year-old female patient presented with severe epigastric pain, found to be attributable to acute pancreatitis. At hospital admission, her serum calcium concentration was high (14.0 mg/dL); the patient also had a normal serum phosphorus level of 3.6 mg/dL and an undetectable PTH level (< 0.2 pmol/L). An evaluation for non-PTH-mediated causes of hypercalcemia revealed a partially suppressed thyroid-stimulating hormone concentration and a below normal 1,25-dihydroxyvitamin D level, consistent with her suppressed PTH. One week after the patient was dismissed from the hospital, repeated laboratory studies showed a serum calcium value of 11.1 mg/dL, a serum phosphorus level of 2.8 mg/dL, and an elevated PTH concentration of 11.0 pmol/L, consistent with primary hyperparathyroidism. A repeated 1,25-dihy-droxyvitamin D measurement was elevated. A parathyroid scan showed a parathyroid adenoma in the left lower neck area, and she subsequently underwent successful surgical resection of a pathologically confirmed parathyroid adenoma.ConclusionThis case demonstrates that the serum PTH level can be suppressed in patients with primary hyperparathyroidism. Moreover, it emphasizes the need for careful evaluation of the clinical context in which the PTH measurement is determined. Consideration should be given to repeating measurement of PTH and serum calcium levels when the initial laboratory evaluation of hypercalcemia is unclear because dynamic changes in calcium metabolism may occur in the presence of secondary contributing factors. (Endocr Pract. 2007;13:785-789)     

Significance of Elevated Parathyroid Hormone After Parathyroidectomy

ObjectiveTo review the prevalence of parathyroid hormone elevation after parathyroidectomy for primary hyperparathyroidism and to discuss possible mechanisms.MethodsA Medline search of the English-language literature published between 1990 and 2009 was performed using the search terms “elevated PTH after parathyroidectomy.” All of the identified articles reported either prospective or retrospective studies without control groups. Studies that included patients with secondary or tertiary hyperparathyroidism were not reviewed.ResultsWithin 1 week to 5 years after parathyroidectomy, 9% to 62% of patients with a normal serum calcium concentration are reported to have an elevated parathyroid hormone concentration. No evidence suggests that postoperative normocalcemic parathyroid hormone elevation is an indication of surgical failure and recurrent hypercalcemia. Preoperative findings in patients with postoperative parathyroid hormone elevation include lower vitamin D concentration, higher concentrations of bone turnover markers, and higher parathyroid hormone concentration. Potential mechanisms for parathyroid hormone elevation in the setting of normocalcemia include vitamin D deficiency, hungry bone syndrome, and parathyroid hormone resistance. Study findings suggest a possible benefit of postoperative calcium and vitamin D supplementation, but no randomized trials have been done.ConclusionElevation of parathyroid hormone commonly occurs after parathyroidectomy for primary hyperparathyroidism, although the underlying mechanism remains unclear. (Endocr Pract. 2010;16:112-117)     

Primary Hyperparathyroidism

ObjectiveTo review primary hyperparathyroidism and the key issues that are relevant to the practicing endocrinologist.MethodsThe latest information on the presentation, diagnosis, and traditional and nontraditional aspects of primary hyperparathyroidism is reviewed.ResultsThe diagnosis of primary hyperparathyroidism is straightforward when the traditional hypercalcemic patient is documented to have an elevated parathyroid hormone (PTH) level. Commonly, patients are identified who have normal serum calcium levels but elevated PTH levels in whom no secondary causes for hyperparathyroidism can be confirmed. Traditional target organs of primary hyperparathyroidism—the skeleton and the kidneys—continue to be a focus in the patient evaluation. Bone mineral density shows a typical pattern of involvement with the distal one-third radius being selectively reduced compared with the lumbar spine in which bone mineral density is generally well maintained. Neurocognitive and cardiovascular aspects of primary hyperparathyroidism, while a focus of recent interest, have not been shown to definitively aid in the decision for or against surgery. The recommendation for surgery in primary hyperparathyroidism is based on guidelines that focus on the serum calcium level, renal function, bone mineral density, and age. In patients who do not meet guidelines, a nonsurgical management approach has merit.ConclusionsPrimary hyperparathyroidism is continuing to show changes in its clinical profile, with normocalcemic primary hyperparathyroidism being a topic of great interest. Skeletal and renal features of primary hyperparathyroidism drive, in most cases, the decision to recommend surgery. In patients who do not meet any criteria for surgery, a conservative approach with appropriate monitoring is acceptable. (Endocr Pract. 2012;18:781-790)     

An Unusual Case of Primary Hyperparath Yroidism with Profoundly Elevated Parath Yroid Hormone Levels

ObjectiveTo report the case of a man who presented with profoundly elevated parathyroid hormone levels in the setting of hypercalcemia, a palpable neck mass, renal disease, and metabolic bone disease.MethodsWe describe the clinical, imaging, and laboratory findings of the patient, including results from genetic testing of the CDC73 gene (HRPT2), and review the relevant literature.ResultsA 28-year-old man with a history of childhood abdominal neuroblastoma treated with chemotherapy and field radiation therapy presented with a 2-week history of persistent left scapular pain and swelling. He had a freely mobile, 1-cm, homogeneous, nontender, firm nodule in the right anterior neck. Parathyroid hormone concentration at hospital admission was 1127 pg/mL. Single-photon emission computed tomography after intravenous administration of technetium Tc 99m–labeled sestamibi revealed an intense focus of abnormal radiotracer uptake on early and delayed images in the right anterior inferior neck. Computed tomography imaging of the chest and neck revealed a 1.9-cm, smooth, calcified nodule posterior to the right lobe of the thyroid gland and diffusely osteopenic bones with trabecular resorption and numerous scattered lucent regions consistent with brown tumors. On bilateral neck exploration, a right inferior parathyroid mass and the left superior parathyroid gland were excised. The remaining 2 parathyroid glands were identified intraoperatively and appeared normal. Genetic testing of the CDC73 gene did not detect germline mutations.ConclusionsThis case highlights the overlap between the clinical findings seen in primary hyperparathyroidism and parathyroid carcinoma. Enhanced understanding of the genetic and molecular bases of primary hyperparathyroidism and parathyroid carcinoma should aid in the diagnosis of these diseases and the care of affected patients. (Endocr Pract. 2008;14:892-897)     

The Clinical Presentation of Primary Hyperparathyroidism: A Southern European Perspective Over the Last 2 Decades

Objective: The clinical presentation of primary hyperparathyroidism (PHPT) has changed widely in developed countries in the last few decades. We evaluated its variations in our series over a 20-year period (i.e., 1997–2016).Methods: A retrospective survey was conducted in our series of 364 well-characterized consecutive patients, arbitrarily divided into 4 consecutive 5-year periods at diagnosis.Results: In the overall series, only estimated glomerular function (eGFR) and urinary calcium (UCa) showed a significant upward trend (P = .032 and .039, respectively), whereas demographic and clinical characteristics were stable. The UCa upward trend was also confirmed for the subgroup of symptomatic patients (P = .013). No difference was observed in the demographic, clinical, or biochemical characteristics of asymptomatic patients or in the fraction of patients meeting surgical criteria.Conclusion: The clinical presentation of PHPT was stable over 20 years in our large series.Abbreviations: Ca = calcium; eGFR = estimated glomerular filtration rate; 25OHD = 25-hydroxyvitamin D; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; UCa = urinary calcium     

Active Crohn Disease and Hypercalcemia Treated With Infliximab: Case Report and Literature Review

ObjectiveTo report a case of 1,25-dihydroxyvitamin D–mediated hypercalcemia caused by active Crohn disease that improved with infliximab therapy.MethodsWe present the clinical and laboratory findings and describe the clinical course of a patient who had hypercalcemia during Crohn disease exacerbations. The literature is reviewed regarding 1,25-dihydroxyvitamin D production in Crohn disease, and the 3 cases of hypercalcemia in individuals with Crohn disease reported in the literature are described.ResultsA 50-year-old man with long-standing Crohn disease treated with multiple bowel resections presented for take-down ileostomy. He was hypercalcemic and had suppressed parathyroid hormone and parathyroid hormone–related peptide levels. Histopathology of the resected ileostomy site and adjacent small bowel indicated active Crohn disease. Hypercalcemia promptly resolved after a few days of treatment with intravenous glucocorticoids. One month later, hypercalcemia recurred in the presence of an inappropriately high 1,25-dihydroxyvitamin D level and increased urinary calcium and serum angiotensin-converting enzyme levels. The serum and urinary calcium levels became normal with infliximab therapy. Three previous reports of hypercalcemia caused by active Crohn disease describe effective treatment with glucocorticoids. This is the first report of successful response to infliximab in this setting.ConclusionHypercalcemia mediated by 1,25-dihydroxyvitamin D in the setting of Crohn disease may respond to glucocorticoid-sparing immunomodulators. (Endocr Pract. 2008;14:87-92)     

Secondary Parathyromatosis in a Patient with Normal Kidney Function: Review of Diagnostic Modalities and Approaches to Management

ObjectiveTo present a patient with secondary parathyromatosis, a rare complication of parathyroidectomy, and to discuss issues currently pertinent to its diagnosis and management.MethodsData were derived from clinical and pathologic observations obtained during patient care.ResultsThe index patient developed intractable hyperparathyroidism and hypercalcemia that has persisted after 4 surgical procedures and has remained largely resistant to medication, albeit with partial amelioration with combined bisphosphonate and cinacalcet.ConclusionDespite the rarity of this difficult complication of parathyroidectomy, its iatrogenic basis emphasizes a need for heightened awareness and caution among surgeons and endocrinologists. Herein we report an instance of intractable secondary parathyromatosis in a patient with normal kidney function, and we review current approaches to diagnosis and management. (Endocr Pract. 2014;20:e4-e7)     

Parathyroid carcinoma arising from four-gland hyperplasia

ObjectiveTo report the use of immunohistochemical staining for parafibromin, APC, and galectin-3 to evaluate the malignant potential of a resected parathyroid specimen in a patient initially presenting with primary hyperparathyroidism attributable to 4-gland hyperplasia, who subsequently developed metastatic parathyroid carcinoma.MethodsWe describe a patient with primary hyperparathyroidism who underwent a 3-gland resection of hypercellular parathyroid glands, with postoperative normalization of her serum calcium and parathyroid hormone levels. She returned 4 years later with recurrent hypercalcemia and underwent partial resection of her remaining hypercellular parathyroid gland, without improvement of her hypercalcemia. Selective venous sampling localized the source as draining into her azygos vein, and metastatic parathyroid carcinoma was ultimately diagnosed.ResultsImmunohistochemical staining for parafibromin, APC, and galectin-3 suggested the malignant potential of the atypical adenoma removed during the patient’s original operation, which is believed to be the source of her metastatic disease. Access to this information by the treating surgeon may have prompted a more extensive en bloc resection or more vigilant follow-up that could have altered the patient’s clinical course.ConclusionImmunohistochemical staining for parafibromin, APC, and galectin-3 can be used to help distinguish the source of metastatic disease in patients with parathyroid carcinoma. Selective venous sampling may help localize metastatic parathyroid carcinoma when the source is otherwise not apparent. (Endocr Pract. 2011;17:e37-e42)     

Albumin-Corrected Calcium and the Prevalence and Categories of Hypercalcemia in Hospitalized Patients With 1-Year Follow-Up of Undiagnosed Cases

ObjectiveTo assess the impact of using corrected calcium versus total calcium on hypercalcemia case detection in hospitalized patients.MethodsPatients hospitalized from June 2012 to June 2017 with a corrected calcium level of ≥10.5 mg/dL were identified by medical record review. One-year follow-up data through June 2018 were acquired. Albumin-corrected calcium level was calculated: (4 − albumin concentration in g/dL) × 0.8 + total serum calcium in mg/dL.ResultsA group of 1067 patients had a corrected calcium level of ≥10.5 mg/dL. The prevalence of hypercalcemia was 0.73% with total calcium and 1.09% with corrected calcium, respectively, with a 49% relative increase. Most patients (62%) had mild hypercalcemia (10.5-11.9 mg/dL); 3.7% had severe hypercalcemia (>14 mg/dL). With corrected calcium, the most common categories of hypercalcemia were malignancy (35.4%), hypercalcemia that was not further evaluated (31.1%), and hyperparathyroidism (22.4%). All patients in the unidentified category had albumin levels <2.8 g/dL. At the 1-year follow–up, 63% of the unidentified cases had normal calcium levels, and 26.8% had mild persistent hypercalcemia. Of those with persisting hypercalcemia at 1 year, 16.8% were diagnosed with hyperparathyroidism.ConclusionUsing albumin-corrected calcium resulted in an ∼50% increase in the detection of hypercalcemia cases. Although hypercalcemia resolved in majority of the undiagnosed cases at 1 year, a number of these remained abnormal. Detecting hypercalcemic disorders by correcting for low albumin level can help identify conditions such as hyperparathyroidism. Adding auto-calculated albumin-corrected calcium to routine laboratory tests could be a cost-effective intervention to improve the detection of hypercalcemic disorders.     

Insertion of an Alu sequence in the Ca(2+)-sensing receptor gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

Missense mutations in the calcium-sensing receptor (CaR) gene have previously been identified in patients with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). We studied family members of a Nova Scotian deme expressing both FHH and NSHPT and found, by PCR amplification of CaR gene exons, that FHH individuals were heterozygous and NSHPT individuals were homozygous for an abnormally large exon 7. This is due to an insertion at codon 877 of an Alu-repetitive element of the predicted-variant/human-specific-1 subfamily. It is in the opposite orientation to the CaR gene and contains an exceptionally long poly(A) tract. Stop signals are introduced in all reading frames within the Alu sequence, leading to a predicted shortened mutant CaR protein. The loss of the majority of the CaR carboxyl-terminal intracellular domain would dramatically impair its signal transduction capability. Identification of the specific mutation responsible for the FHH/NSHPT phenotype in this community will allow rapid testing of at-risk individuals.     

Efficacy of Teriparatide in Patients with Resolved Secondary Hyperparathyroidism due to Vitamin D Deficiency

ObjectiveTo determine the efficacy of at least 1 year of teriparatide therapy on bone mineral density (BMD), T-scores, and rates of occurrence of fractures in patients with a history of resolved secondary hyperparathyroidism due to vitamin D deficiency and to compare its efficacy with that in patients without a history of resolved secondary hyperparathyroidism.MethodsIn this retrospective study based on a search of electronic medical records, we collected the following data: patient demographics, doses of calcium and vitamin D supplementation, duration of teriparatide treatment, history and treatment of secondary hyperparathyroidism, BMD information, T-scores, and any history of fractures. Paired and unpaired t tests, the Fisher exact test, and the Wilcoxon rank sum test were used for statistical analysis.ResultsNinety-five patients (7 with a history of resolved secondary hyperparathyroidism due to vitamin D deficiency and 88 without such a history) fulfilled the study inclusion criteria. Baseline characteristics (demographics, median calcium and vitamin D supplementation doses, mean BMD, mean T-scores, and fracture rates before Submitted for publication July 31, 2010 Accepted for publication January 13, 2011 teriparatide therapy) were similar between the 2 groups. In comparison with baseline data, after a mean of 21 months of teriparatide therapy: (1) hip BMD and T-scores did not change in either study group (with no significant differences between the 2 groups), (2) spine BMD and T-scores significantly improved in both study groups (with no significant differences between them), and (3) wrist T-scores significantly worsened in both study groups (with wrist BMD significantly lower in patients without a history of secondary hyperparathyroidism). No patients with a history of secondary hyperparathyroidism sustained a fracture while receiving teriparatide therapy versus 6 of 88 patients without a history of secondary hyperparathyroidism (P = .624).ConclusionPatients with a history of resolved secondary hyperparathyroidism attributable to vitamin D deficiency responded to teriparatide therapy in a fashion similar to patients without such a history. (Endocr Pract. 2011;17:568-573)     

Primary Hyperparathyroidism in the Young: Comparison with Adult Primary Hyperparathyroidism

Objective: Primary hyperparathyroidism (PHPT) is relatively common among adults but rarely encountered in children and adolescents. According to the western literature, young PHPT is different from adult PHPT and is associated with more severe hypercalcemia. PHPT in the adult Indian population is different from its western counterpart. Here we present the clinical, biochemical, and surgical characteristics of young patients with PHPT treated at our tertiary care center.Methods: PHPT patients were divided into adult (≥25 years) and young (<25 years) groups. The clinical, biochemical, hormonal, and histopathologic characteristics and treatment outcomes in the groups were compared.Results: Out of 358 patients, 47 patients were young and 311 patients were adults. The mean ages of the groups were 19 ± 4 and 45 ± 12 years, respectively. The corresponding female-to-male ratios were 1.24:1 and 3.38:1 (P<.05). The nature and frequency of presenting symptoms were comparable between the 2 groups. The most common symptom in young patients with PHPT was bone pain and was not significantly different from adults (57% vs. 61%, respectively). The most common symptom in adult PHPT was fatigue, which was also not significantly different from young patients (63% vs. 53%, respectively), The serum calcium, phosphate, 25-hydroxyvitamin D levels; alkaline phosphatase Z-score; and parathyroid hormone levels were comparable between the 2 groups. Parathyroid adenoma was the most common histopathologic finding, while hyperplasia was rare in both groups.Conclusion: We observed that young PHPT is not markedly different from its adult counterpart in an Indian population.Abbreviations: ALP = alkaline phosphatase; Ca = calcium; Cr = creatinine; iPTH = intact parathyroid hormone; 25(OH)D = 25-hydroxyvitamin D; P = phosphate; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; RR = reference range; ^99mTc sestamibi = technetium sestamibi; USG = ultrasonography     

AN AGGRESSIVE TEMPORAL BONE SDHC PARAGANGLIOMA ASSOCIATED WITH INCREASED HIF-2α SIGNALING

Objective: To describe a patient with a germline succinate dehydrogenase (SDHC) gene mutation presenting with primary hyperparathyroidism and a large catecholamine-producing temporal bone paraganglioma (PGL).Methods: Evaluation of a SDHC mutation–positive PGL tumor biology using staining for tyrosine hydroxylase (TH), hypoxia-inducible factors 1α (HIF-1α) and 2α (HIF-2α).Results: A 66-year-old man was noted to have a lytic skull base mass during work-up for his primary hyperparathyroidism. Biochemical evaluation with 24-hour urine catecholamines and metanephrines revealed marked elevation of norepinephrine and normetanephrine. Genetic testing revealed a germline SDHC mutation. A partial excision of skull base tumor was performed, which upon further examination revealed PGL. Immunohistochemistry of skull base PGL demonstrated heavy expression of TH and HIF-2α but reduced expression of HIF-1α. The remaining skull base PGL was treated with adjuvant radiation therapy. The patient's normetanephrine levels significantly decreased after surgery and radiation.Conclusion: Here, we report an unusual case of a patient presenting with a germline SDHC mutation–related functional PGL along with concomitant primary hyperparathyroidism. The present case illustrates that overexpression of HIF-2α but not of HIF-1α is linked to the pathogenesis of SDHC mutation–related PGL, and it may be responsible for the aggressive clinical behavior of a usually indolent course of SDHC-related PGLs.Abbreviations:HIF = hypoxia-inducible factorMEN2A = multiple endocrine neoplasia type 2aPCC = pheochromocytomaPGL = paragangliomaPTH = parathyroid hormoneSDH = succinate dehydrogenaseTH = tyrosine hydroxylase     

Urinary Calcium Excretion in Primary Hyperparathyroidism: Relationship to 25-Hydroxyvitamin D Status

ObjectiveTo determine the prevalence of vitamin D deficiency in patients with primary hyperparathyroidism (PHPT) and evaluate the relationship between urinary calcium excretion and serum 25-hydroxyvitamin D (25-OH-D) levels in patients with PHPT.MethodsWe present a case report and a review of the medical records of patients with PHPT. Of 75 patients with PHPT substantiated by hypercalcemia and increased levels of intact parathyroid hormone (iPTH), 35 were identified with laboratory evaluation of vitamin D levels and 24-hour urinary calcium excretion. These study subjects were stratified as 25-OH-D deficient, insufficient, or replete (on the basis of serum values of < 15, 15 to 25, or > 25 ng/mL, respectively). Total 24-hour urinary calcium excretion and the fractional excretion of calcium (FECa) were analyzed as a function of 25-OH-D status.ResultsOf the 35 study subjects, 14 (40%) and 13 (37%) had 25-OH-D deficiency or insufficiency, respectively. Those patients with a 25-OH-D level < 15 ng/mL had higher serum iPTH concentrations as well as lower urinary calcium excretion and FECa. No significant correlations were found, however, between 25-OH-D status and iPTH concentrations (r = -0.21; P = 0.23), total 24-hour urinary calcium excretion (r = 0.07; P = 0.7), or FECa (r = 0.04; P = 0.8).ConclusionVitamin D deficiency (25-OH-D levels < 15 ng/mL) was common in our population of patients with PHPT. Urinary calcium excretion was not significantly altered by 25-OH-D deficiency in patients with newly recognized PHPT. Measurements of total urinary calcium excretion and FECa can be reliably used to rule out familial benign hypocalciuric hypercalcemia in the initial evaluation of PHPT, regardless of 25-OH-D status. Determining 25-OH-D concentrations best assesses the vitamin D status. (Endocr Pract. 2005;11:37-42)