COLLISION DIAGNOSES: PRIMARY HYPERPARATHYROIDISM LAYERED ON FAMILIAL HYPOCALCIURIC HYPERCALCEMIA

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1 Case Report COLLISION DIGNOSES: PRIMRY HYPERPRTHYROIDISM LYERED ON FMILIL HYPOCLCIURIC HYPERCLCEMI Seth Kay, MD 1 ; Mara Piltin, DO 2 ; Vicoria Loseva, MD 3 ; ridget Sinnott, MD 3 ; J. Robert rennan, MD 4 ; Swati Mehrotra, MD 5 ; David Terris, MD, FCE, FCS 1,3 STRCT Objective: Describe the presentation, work-up, and management of a rare co-occurrence of familial hypocalciuric hypercalcemia (FHH) and primary hyperparathyroidism (PHPT) in a single patient. dditionally, to explore the challenges in diagnosing in such patients, summarize the previous literature on this uncommon occurrence, and explore the possible etiologies for it. Methods: Case presentation from a tertiary care academic medical system. Results: Successful diagnosis and surgical management, returning the patient to his previously asymptomatic FHH baseline. Conclusion: FHH and PHPT are both causes of hypercalcemia. Very rarely, these two conditions can occur simultaneously in the same patient. The relationship between these two entities when they present concurrently is complex, likely the result of particular CSR mutations Submitted for publication January 3, 2018 ccepted for publication February 28, 2018 From the 1 Department of Otolaryngology Head & Neck Surgery, ugusta University Medical Center, ugusta, Georgia, 2 Department of General Surgery, Rowan University School of Osteopathic Medicine, Stratford, New Jersey, 3 Section of Endocrinology, ugusta University Medical Center, ugusta, Georgia, 4 Laurel Endocrine & Thyroid, Columbia, South Carolina, and 5 Department of Pathology, Loyola University Medical Center, Maywood, Illinois. ddress correspondence to Dr. Seth Kay, 616 West Fulton Street #717, Chicago, IL stskay@gmail.com. DOI: /CCR To purchase reprints of this article, please visit: Copyright 2018 CE. causing greater parathyroid cellular proliferation and an increased predisposition to developing PHPT. These rare patients can be difficult to diagnose, but when recognized appropriately and managed with surgery for the PHPT component, they can achieve an asymptomatic FHH state. (CE Clinical Case Rep. 2018;4:e362-e366) bbreviations: CSR = calcium-sensing receptor gene; CaSR = calcium-sensing receptor protein; DX = dual-energy X-ray absorptiometry; FEca = fractional excretion of calcium; FHH = familial hypocalciuric hypercalcemia; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone INTRODUCTION Familial hypocalciuric hypercalcemia (FHH) and primary hyperparathyroidism (PHPT) are separate and distinct etiologies, each of which may result in hypercalcemia. ccordingly, the respective approaches to their management vary considerably: medical therapy is pursued for FHH and surgical treatment is usually needed for PHPT. The ability to distinguish between the two is therefore critical. This is sometimes challenging, as their presentations are often similar and their biochemical profiles may overlap. Contributing additional difficulty to this diagnostic dilemma is the rare co-occurrence of both disease processes in the same patient. To date, nine such cases have been published in the literature. The goal of this paper is to discuss our experience with the presentation and management of one such patient, put this in the context of the previous reports, and explore causative versus coincidental relationships between the two conditions. e362 CE CLINICL CSE REPORTS Vol 4 No. 5 September/October 2018 Copyright 2018 CE

2 Copyright 2018 CE Concurrent FHH and PHPT, CE Clinical Case Rep. 2018;4(No. 5) e363 CSE REPORT 53-year-old asymptomatic male presented with a history of FHH and worsening hypercalcemia. Work-up for hypercalcemia began 3 years prior, with a serum calcium level of 11.1 mg/dl (normal range, 8.5 to 10.2 mg/dl), parathyroid hormone (PTH) 29 pg/ml (normal range, 10 to 65 pg/ml), 25-hydroxyvitamin D of 63 ng/ml (normal range, 20 to 100 ng/ml), 1,25-dihydroxyvitamin D of 90 pg/ml (normal range, 18 to 72 pg/ml), 24-hour urine calcium 56 mg/day (normal range, 100 to 250 mg/day), and fractional excretion of calcium (FEca) Suspected FHH was confirmed, with genetic testing revealing a previously unreported c.2208g>c; p.gly670rg mutation in the calciumsensing receptor gene (CSR). His mother, three siblings, and his son were screened and all found to be eucalcemic (no genetic testing was performed). Under routine surveillance a year later, his serum calcium levels increased to 12.2 mg/dl and his PTH rose to 45 pg/ml. Sestamibi scan performed at an outside institution was nonlocalizing. He was started on cinacalcet to help reduce his serum calcium levels. Despite 10 months of therapy on high-dose cinacalcet (90 mg twice a day), his serum calcium level continued to rise to 13.7 mg/dl, and the medication was eventually discontinued secondary to cost and ineffectiveness. One year later, his serum calcium was 15.2 mg/dl, PTH 159 pg/ml, 1,25-dihydroxyvitamin D 72 pg/ml, 24-hour urine calcium 296 mg/day, and FEca Dual-energy X-ray absorptiometry (DX) revealed osteopenia at the femoral neck (T-score, 1.7). Further work-up with a single-photon emission computed tomography sestamibi scan at ugusta University revealed uptake in the deep right inferior quadrant, likely representing an overly descended right superior parathyroid adenoma (Fig. 1). Ultrasound colocalized with a hypoechoic lesion measuring cm inferior and deep to the right thyroid lobe (Fig. 2). It was suspected that PHPT had developed, superimposed on his previously established FHH. Given his extremely elevated serum calcium levels, bone loss documented on DX, and colocalizing sestamibi and ultrasound studies, the decision was made to perform a parathyroidectomy. n overly descended right superior parathyroid adenoma was identified and resected (Fig. 3). ecause of the history of his baseline FHH, a four-gland exploration was performed. The remaining three glands were identified in eutopic locations and judged to be normal in size, color, and substance (Fig. 3). Each gland was biopsied and sent for permanent pathology. baseline intra-operative PTH level was pg/ml, and post adenoma excision levels were 32.8 pg/ml at 5 minutes and 25.2 pg/ml at 10 minutes, indicating biochemical cure of the PHPT component of his hypercalcemia. Pathology confirmed that the overly descended right superior parathyroid gland was an adenoma (Fig. 4), and the biopsies of the three normalappearing parathyroid glands revealed hypercellular parathyroid tissue. Labs drawn 1 month after his surgery indicated a serum calcium of 10.7 mg/dl and PTH of 19 pg/ ml, confirming cure of his PHPT and a return to his baseline FHH biochemical profile. DISCUSSION FHH is most commonly caused by one of over 150 mutations identified in the CSR. CSR mutations display an autosomal dominant pattern of inheritance, with heterozygous individuals manifesting FHH and homozygous individuals suffering from neonatal severe hyperparathyroidism (1). CSR mutations result in loss of function of Fig. 1. Coronal views of a single-photon emission computed tomography sestamibi scan. () Immediate imaging revealing enhancement (white arrow) in the right inferior quadrant. () Persistent enhancement (white arrow) on delayed (2.5 hours) imaging in the right inferior quadrant adjacent to the spine, consistent with an overly descended right superior parathyroid adenoma.

3 e364 Concurrent FHH and PHPT, CE Clinical Case Rep. 2018;4(No. 5) Copyright 2018 CE the calcium-sensing receptor (CaSR) protein. The CaSR is located in the parathyroid glands (acting to regulate PTH secretion) and kidneys (modulating renal tubular calcium re-absorption), resulting in tightly regulated serum calcium levels (2). Loss of CaSR function causes a shift of the calcium set point (resulting in mild to moderate hypercalcemia), higher calcium levels necessary to suppress PTH secretion (manifesting as nonsuppressed to slightly elevated PTH levels), and increased calcium re-absorption in the kidney (exhibited by relative hypocalciuria) (1). Despite these biochemical changes, FHH patients remain clinically asymptomatic. Treatment for FHH patients is close observation with dietary and medication modifications. Surgery is contra-indicated as it does not resolve the hypercalcemia, nor does it provide any other clinical benefit. PHPT is caused by the inappropriate secretion of PTH by parathyroid glands despite the presence of hypercalcemia (2). Eighty-five percent of the time, this is the result of autonomous production by a single parathyroid adenoma, 10% by double adenomas, and 5% by four-gland hyperplasia (3). This condition classically presents with mild to severe hypercalcemia, PTH levels ranging from nonsuppressed high normal to highly elevated, and normal to increased urine calcium levels. Chronically elevated PTH levels can cause bone loss, and long-term hypercalcemia can lead to nephrolithiasis and kidney failure. Patients Fig. 2. Ultrasound of the right thyroid lobe. () Transverse view demonstrating a 0.94-cm hypoechoic lesion (white dotted line) deep to the right thyroid and carotid (Ca = carotid, Thyr = thyroid). () Longitudinal view demonstrating a 1.41-cm hypoechoic lesion (white dotted line) deep and along the inferior aspect of the right thyroid, likely representing an overly descended right superior parathyroid adenoma (Thyr = thyroid). C D Fig. 3. Intra-operative photos. () Overly descended right superior parathyroid adenoma (white arrow). () Right inferior parathyroid gland (white arrow). (C) Left superior parathyroid gland (white arrow). (D) Left inferior parathyroid gland (white arrow).

4 Copyright 2018 CE Concurrent FHH and PHPT, CE Clinical Case Rep. 2018;4(No. 5) e365 Fig. 4. Photomicrographs of the right superior parathyroid adenoma (hematoxylin and eosin stain). () Low-power view of parathyroid adenoma depicting a cellular neoplasm surrounded by a thin capsule with a rim of compressed normal gland on the left (thick black arrow). Note the conspicuous absence of fat within the adenoma, which is limited to the adjacent normal gland (thin black arrow). () High-power view of parathyroid adenoma composed exclusively of nests of chief cells separated by delicate fibrovascular septa. The chief cells have central round nuclei, inconspicuous nucleoli, and eosinophilic to clear cytoplasm. may also develop musculoskeletal, gastrointestinal, neuropsychiatric, and cardiovascular manifestations. With the advent of routine biochemical screening of calcium levels, PHPT is now diagnosed more commonly at an earlier, asymptomatic stage. Surgery is the recommended treatment for symptomatic patients (pathologic fracture, osteitis fibrosa cystica, neuromuscular syndrome, or nephrolithiasis) and most asymptomatic patients. Observation without surgery is contra-indicated in patients who have findings as discussed by the international guidelines published in 2014 (serum calcium >1.0 mg/dl above the upper limit of normal, osteoporosis on DX scan, vertebral fracture on imaging, creatinine clearance <60 ml/min, 24-hour urine calcium >400 mg/day, age <50 years) (4). Surgery is the only definitive therapy, with success resulting in serum calcium and PTH levels returning to normal ranges and reduction of symptom manifestation. PHPT predominantly develops sporadically, the result of CaSR downregulation classically without an associated somatic mutation (5). It far less commonly occurs in hereditary forms such as familial isolated hyperparathyroidism, hyperparathyroidism jaw tumor syndrome, and multiple endocrine neoplasia syndromes I and IIa. Differentiation between FHH and PHPT involves a detailed history and confirmatory laboratory studies. Classic features of FHH on biochemical analysis (mild hypercalcemia and nonsuppressed normal to slightly elevated PTH) now overlap considerably with recognized variants of classic PHPT (both normocalcemic and normohormonal). Suspicion is raised for FHH when 24-hour urine calcium levels are <100 mg/day (1). Further distinction between the two can be made with evaluation of urinary calcium to creatinine ratio (also known as FEca). Classically, FEca <0.01 is suggestive of FHH and should be confirmed with genetic testing (6). However, 15 to 20% of FHH patients have FEca >0.01 (5), and 10 to 20% of PHPT patients have FEca <0.01 (1), with considerable overlap of the two conditions in the ranges between <0.02 and Some authors suggest genetic testing in this overlapping range (7). Negative pre-operative localizing studies can neither effectively rule in FHH nor rule out PHPT (8-10). Pathologic analysis of resected parathyroid glands in FHH has typically revealed normal-sized glands and a spectrum of histologic findings ranging from normocellular parathyroid tissue to moderate hypercellularity (6,11). FHH is not associated with adenoma formation on pathologic analysis (2). Further complicating the differentiation between FHH and PHPT is the rare co-occurrence of both conditions in the same patient. Including this case report, nine such cases have been published in the literature thus far (1-3,5-7). These unique patients tend to present in one of two ways: long-standing FHH with gradually worsening hypercalcemia and rising PTH levels (4 patients, including our own), or a newly diagnosed hypercalcemic patient with overlapping biochemical profiles (5 patients). In the case of the latter presentation, either careful initial workup elucidated the concurrent diagnosis (3 patients), or FHH was discovered during the work-up of persistently elevated calcium levels after successful parathyroidectomy (2 patients). ll 9 patients underwent successful surgery for single parathyroid adenomas, confirmed on pathology. side from our patient, pathologic inspection of the remaining three glands was not performed. The postop-

5 e366 Concurrent FHH and PHPT, CE Clinical Case Rep. 2018;4(No. 5) Copyright 2018 CE erative calcium levels decreased (but did not normalize) and in all patients PTH levels fell into the normal range, demonstrating a classic FHH biochemical profile. ll but one patient experiencing musculoskeletal, gastrointestinal, and/or neuropsychiatric symptoms reported improvement or resolution of these symptoms postoperatively. The relationship between FHH and PHPT when they present concurrently remains unclear. Whether it is a simple coincidental co-existence of the two disorders or a complex relationship with CSR mutations causing the initiation or progression of PHPT is an ongoing debate (12). If it was simply a matter of statistical coincidence, urski et al (6) estimate the incidence of co-occurrence to be 1:10,000,000 patients, which is consistent with the low number of reported cases in the literature. If there was direct causality, one would expect that all family members with the same CSR mutation would also develop PHPT (which Egan et al [2] have shown not to be the case) or that multiple adenomas would be appreciated in these patients given that cells in all four parathyroid glands possess the same somatic mutation (which has not been reported). While somatic mutations in CSR are not found in parathyroid adenomas (13), it has clearly been established that a relationship does exist between the downregulation of the CaSR and proliferation of parathyroid cells, resulting in PHPT (5). Frank-Raue et al (13) have therefore speculated that some CSR mutations may have a more positive effect on parathyroid cell proliferation than others and therefore cause a greater predisposition to develop PHPT. CONCLUSION FHH and PHPT are both causes of hypercalcemia. While their respective etiologies and management are distinct, they often present similarly and differentiation between the two can sometimes be difficult. Complicating matters further is the rare co-occurrence of both conditions in the same patient. The relationship between these two entities when they present concurrently is complex, likely the result of particular CSR mutations causing greater parathyroid cellular proliferation and an increased predisposition to developing PHPT. These rare patients can be difficult to diagnose, but when recognized appropriately and managed with surgery for the PHPT component, they can achieve an asymptomatic FHH state. DISCLOSURE The authors have no multiplicity of interest to disclose. REFERENCES 1. Eldeiry LS, Ruan DT, rown EM, Gaglia JL, Garber JR. Primary hyperparathyroidism and familial hypocalciuric hypercalcemia: relationships and clinical implications. Endocr Pract. 2012;18: Egan M, Ryan J, zizi M, O Dwyer TP, yrne MM. Primary hyperparathyroidism in a patient with familial hypocalciuric hypercalcemia due to a novel mutation in the calcium-sensing receptor gene. J one Miner Metab. 2013;31: rachet C, oros E, Tenoutasse S, et al. ssociation of parathyroid adenoma and familial hypocalciuric hypercalcemia in a teenager. Eur J Endocrinol. 2009;161: ilezikian JP, randi ML, Eastell R, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99: Forde HE, Hill D, Smith D. Parathyroid adenoma in a patient with familial hypocalciuric hypercalcemia. MJ Case Rep. 2014; urski K, Torjussen, Paulsen Q, oman H, ollerslev J. Parathyroid adenoma in a subject with familial hypocalciuric hypercalcemia: coincidence or causality? J Clin Endocrinol Metab. 2002;87: Yabuta T, Miyauchi, Inoue H, Yoshida H, Hirokawa M, mino N. patient with primary hyperparathyroidism associated with familial hypocalciuric hypecalcemia induced by a novel germline CaSR mutation. sian J Surg. 2009;32: Eastell R, randi ML, Costa G, D mour P, Shoback DM, Thakker RV. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinl Metab. 2014;99: Law WM Jr, James EM, Charboneau JW, Purnell DC, Heath H 3rd. High resolution parathyroid ultrasonography in familial benign hypercalcemia (familial hypocalciuric hypercalcemia). Mayo Clin Proc. 1984;59: Wu S, Hwang SS, Haigh PI. Influence of a negative sestamibi scan on the decision for parathyroid operation by the endocrinologist and surgeon. Surgery. 2017;161: Law WM Jr, Carney J, Heath H 3rd. Parathyroid glands in familial benign hypercalcemia (familial hypocalciuric hypercalcemia). m J Med. 1984;76: Guarnieri V, Canaff L, Yun F, et al. Calcium-sensing receptor (CSR) mutations in hypercalcemic states: studies from a single endocrine clinic over three years. J Clin Endocrinol Metab. 2010;95: Frank-Raue K, Leidig-ruckner G, Haag C, et al. Inactivating calcium-sensing receptor mutations in patients with primary hyperparathyroidism. Clin Endocrinol (Oxf). 2011;75:50-55.