Joint Bone Spine 82 (2015) 60–62
Available online at
ScienceDirect www.sciencedirect.com
Case report
Familial hypocalciuric hypercalcemia associated with crystal deposition disease Lilian Alix a , Pascal Guggenbuhl b,c,d,∗ a
Service de médecine interne, hôpital sud, centre hospitalier universitaire, 35000 Rennes, France INSERM UMR 991, 35000 Rennes, France Service de rhumatologie, hôpital Sud, CHU, 35000 Rennes, France d Université de Rennes 1, 35000 Rennes, France b c
a r t i c l e
i n f o
Article history: Accepted 22 August 2014 Available online 13 October 2014 Keywords: Familial Hypocalciuric Hypercalcemia Chondrocalcinosis Calcium-sensing receptor
a b s t r a c t Chondrocalcinosis is a common disease occasionally associated with hypercalcemia in case of primary hyperparathyroidism. Familial Hypocalciuric Hypercalcemia (FHH) is a rare and almost always asymptomatic condition, due to an autosomal dominant mutation of the calcium-sensing receptor gene. We report the case of a 61-year-old female with chronic hypercalcemia and joint pain. Clinical and biological data revealed chondrocalcinosis associated with FHH. Since primary hyperparathyroidism may mimic FHH, calcium to creatinine clearance ratio should be calculated in every case to avoid a wrong diagnosis and useless parathyroid surgery. The paucity of FFH complications, including chondrocalcinosis, makes their study difficult: additional studies are needed to clearly evaluate the link between FHH and chondrocalcinosis. © 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Familial Hypocalciuric Hypercalcemia (FHH), also known as Marx’s syndrome, was first documented in 1966 by Jackson and Boonstra and fully described in 1972 by Foley et al. It is a rare and benign condition–its prevalence is estimated at 1 in 78,000 people in West Scotland [1]. Genetic inheritance is autosomal dominant. It is characterized by an inactivating mutation of the calcium-sensing receptor (CaSR) gene. The CaSR is a protein-coupled receptor of 1078 amino acids, expressed in many tissues but mostly in parathyroid glands, kidneys and bones. So far, 139 inactivating mutations have been described [2]. CaSR senses extracellular calcium level to adjust urinary calcium level and parathyroid hormone (PTH) synthesis and excretion. Thus, a rise of calcium serum level leads to increased calcium urine excretion and decreased PTH synthesis [3]. In FHH, the inactivating mutation causes a loss of function of the CaSR and affects many tissues. Parathyroid cells become less sensitive to a rise in serum ionized calcium. Indeed, PTH secretion persists even if the calcium serum level is high and a higher calcium serum level is needed to suppress PTH secretion.
∗ Corresponding author. E-mail address: [email protected] (P. Guggenbuhl).
CaSR is expressed in kidneys in almost every part of the nephron. The inactivating mutation decreases sensitivity of kidney cells to serum and urine calcium levels. This leads to an enhanced tubular reabsorption of calcium and thereby reduces calcium urine excretion. Since creatinine clearance is not affected by the disease, calcium urine excretion can be easily evaluated using the calcium to creatinine clearance ratio (CCCR): CCCR = (Cau × Crs )/(Cas × Cru ). This ratio is a key diagnosis criterion if < 0.01. CaSR loss of function does not affect the balance between osteoclastic and osteoblastic function. There is no osteoclastic activation as observed in primary hyperparathyroidism (PHPT). That is why Bone Mineral Density (BMD) is most often normal in FHH in contrast to PHPT [4]. Furthermore, some physiopathological aspects of FHH remain unclear and other cells, such as osteocytes and lining cells, may be involved. Chondrocalcinosis (CC) is characterized by calcium pyrophosphate dehydrate crystal deposition in joints. It can be revealed by mono- or polyarthritis but can also be asymptomatic. While it is a common disease, its epidemiology is poorly known. Prevalence is higher with aging. According to the Framingham Osteoarthritis Study, knee radiological involvement is approximately 3% between 65 and 69 years of age while it rises up to 27% beyond 85 years of age [5]. Most CCs are idiopathic, but there are secondary forms mainly due to PHPT, hemochromatosis, hypomagnesemia, hypophosphatasia or familial diseases.
http://dx.doi.org/10.1016/j.jbspin.2014.08.007 1297-319X/© 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
L. Alix, P. Guggenbuhl / Joint Bone Spine 82 (2015) 60–62
Fig. 1. Meniscal calcifications in both knees.
FHH association with CC was first described by Health in 1989 [6]. To our knowledge, only one other case has been reported since [7].
61
Our patient was tested for a mutation of the CaSR gene: a missense mutation in the second exon of the CaSR gene was identified (c.157T > C; p.S53P), confirming the diagnosis of FHH. Additional research revealed that one of the patient’s sisters had a diagnosis of chronic hypercalcemia with hypocalciuria in 1992 (serum calcium level was at 2.8 mmol/L and CCCR 0.009) and that she has the same mutation of the CaSR gene. She also has a mutation of the seventh exon (c.2956G > T; p.A986S): this mutation is associated with hypercalcemia but is not related to FHH [2,8]. After a 6-year follow-up, polyarthralgia (especially of wrists and knees) remained but seemed to be less active. The patient had been successfully treated with acetaminophen and occasionally nefopam. Since colchicine was ineffective, it had been stopped. In the last assessment, hypercalcemia remained (2.78 mmol/L) without sign of acute hypercalcemia. PTH was still in the normal range, CCCR was 0.013. BMD was steady without antiresorptive drugs.
2. Case report
3. Discussion
We report the case of a 61-year-old female who was referred to our department to undergo clinical investigations concerning hypercalcemia associated with chronic polyarthralgia. She complained of joints pain that had been affecting wrists, knees, ankles and upper spine for ten years. She had several short accesses of joint pain (3–4 days) a year. She had no sign of acute hypercalcemia. She reported hypercalcemia in a brother, a sister, and her daughter. Physical examination was normal; there was no joint tenderness or swelling. Biological tests indicated mild hypercalcemia (2.75 mmol/L). Phosphatemia was normal (1.02 mmol/L), so was PTH level (29 pg/mL) while 25-OH Vitamine D was slightly lowered (23 ng/mL). PTH-related peptide and blood protein electrophoresis were both normal. CCCR was 0.017. Joint X-rays showed chondrocalcinosis of knees (Fig. 1), right wrist (Fig. 2) and pubic symphisis. Parathyroid ultrasound and scintigraphy were both normal. CT-scan revealed a 9 mm adrenal gland adenoma but did not report any ectopic parathyroid adenoma. DXA showed osteopenia (T-score at hip = –1.4 SD, femoral neck = –1.5 SD). Hypercalcemia was initially treated with an infusion of pamidronate (30 mg) and saline infusions. Joint pain was treated by colchicine (1 mg/day) and acetaminophen. Three months later, pain was unchanged. Hypercalcemia persisted (2.85 mmol/L) while PTH was still normal (36 pg/mL). A second perfusion of pamidronate 30 mg was administered to the patient. She also underwent a full screening in the department of endocrinology, including a pituitary MRI: it was concluded to a benign adrenal gland adenoma. There was no evidence of Multiple Endocrine Neoplasia (MEN).
FHH is a benign asymptomatic condition in most cases. Despite hypercalcemia, patients have a normal life expectancy. Very few complications had been described in FHH. Gallstones, pancreatitis and CC were the most common. In our case, there were no arguments for a secondary form of CC: ferritin level (56 ng/mL) and transferrin saturation (39%) were both normal, excluding hemochromatosis. Alkaline phosphatase (65 IU/L) and magnesemia were also normal (0.86 mmol/L), ruling out hypophosphatasia and hypomagnesemia. Furthermore, our patient was quite young when the first symptoms began (approximately 50 years old), as was the patient in the other reported case of CC associated with FHH (58 years old). Those relatively young ages go against idiopathic CC. It is, nevertheless, impossible to prove whether those diseases are really due to FHH and are not fortuitously associated. In addition, it is interesting to notice that clinical presentation was different since the other patient had recurrent arthritis while ours did not. The long period between first symptoms and diagnosis (10 years in our case, 20 years in Volpe’s) may demonstrate the lack of knowledge concerning FHH. Since FHH may mimic PHPT, the main challenge is to make the diagnosis of FHH, to avoid a parathyroidectomy which is not indicated as it does not cure the patient and as it may imply postoperative complications. In a recent review, Christensen notices that up to 23% of unnecessary parathyroid surgeries could be found in FHH [9]; 10% in Health’s study [6] and 9% in Marx’s [10]. That is why a 24 h urine sample should be performed in any case of PHPT suspicion to calculate the CCCR and to lead the physician to the diagnosis of FHH sparing parathyroid surgery. A CCCR < 0.01 is a strong argument for FHH and should lead to further genetic investigations to confirm the diagnosis. In PHPT, CCCR is below 0.01 in only 4% of cases [11]. A CCCR > 0.02 should exclude FHH. Between 0.01 and 0.02, diagnosis is uncertain. According to Christensen, the 0.01 cut-off is not satisfying: up to 35% of FHH patients (as our patient) have a CCCR between 0.01 and 0.02. This strategy has a sensitivity of 98% [9]. If there is no identified mutation (in up to 82% of cases), other genetic investigations are recommended if there is a familial history of hypercalcemia. Those patients should be screened for MEN: MEN1 (menin gene), MEN-2 (RET gene) and for hyperparathyroidism 2 (HRPT-2 gene). In the absence of familial history, parathyroid surgery must be discussed. It is important that imaging examinations are made by trained operators and that vitamin D and/or diuretic drugs are stopped 5 days before blood and urine samples collection. A 24 h urine sample is essential, since a spot urine sample has been proved not to be reliable enough [10,12].
Fig. 2. Calcification of right wrist ligament.
62
L. Alix, P. Guggenbuhl / Joint Bone Spine 82 (2015) 60–62
It is also crucial that FHH patients inform their families in order to diagnose FHH in the other members of the family to spare useless and costly investigations and prevent parathyroid surgery. The physician has a key role to play here. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Cetani F, Pardi E, Borsari S, et al. Two Italian kindreds with familial hypocalciuric hypercalcemia caused by loss-of-function mutations in the calcium-sensing receptor (CaR) gene: functional characterization of a novel CaR missense mutation. Clin Endocrinol (Oxf) 2003;58:199–206. [2] http://www.casrdb.mcgill.ca/. [3] Brown EM, MacLeod RJ. Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev 2001;81:239–97. [4] Abugassa S, Nordenstrom J, Jarhult J. Bone-mineral density in patients with familial hypocalciuric hypercalcaemia (FHH). Eur J Surg 1992;158:397–402.
[5] Felson DT, Naimark A, Anderson J, et al. The prevalence of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study. Arthritis Rheum 1987;30:914–8. [6] Heath III. H. Familial Benign (Hypocalciuric) Hypercalcemia: a troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am 1989;18:723–40. [7] Volpe A, Guerriero A, Marchetta A, et al. Familial hypocalciuric hypercalcemia revealed by chondrocalcinosis. Joint Bone Spine 2009;76:708–10. [8] Heath III H, Odelberg S, Jackson CE, et al. Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains. J Clin Endocrinol Metab 1996;81:1312–7. [9] Christensen S, Nissen P, Vestergaard P, et al. Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes 2011;18: 359–70. [10] Marx SJ, Stock JL, Attie MF, et al. Familial hypocalciuric hypercalcemia: recognition among patients referred after unsuccessful parathyroid exploration. Ann Intem Med 1980;92:351–6. [11] Christensen SE, Nissen PH, Vestergaard P, et al. Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods. Clin Endocrinol (Oxf) 2008;69:713–20. [12] Cegla J, Saroya S, McGowan B, et al. Is it time to replace the 24 h urine calcium: creatinine clearance ratio in the investigation of PTH-dependent hypercalcaemia. Endocr Abstr 2010;21:13.
Available online at
ScienceDirect www.sciencedirect.com
Case report
Familial hypocalciuric hypercalcemia associated with crystal deposition disease Lilian Alix a , Pascal Guggenbuhl b,c,d,∗ a
Service de médecine interne, hôpital sud, centre hospitalier universitaire, 35000 Rennes, France INSERM UMR 991, 35000 Rennes, France Service de rhumatologie, hôpital Sud, CHU, 35000 Rennes, France d Université de Rennes 1, 35000 Rennes, France b c
a r t i c l e
i n f o
Article history: Accepted 22 August 2014 Available online 13 October 2014 Keywords: Familial Hypocalciuric Hypercalcemia Chondrocalcinosis Calcium-sensing receptor
a b s t r a c t Chondrocalcinosis is a common disease occasionally associated with hypercalcemia in case of primary hyperparathyroidism. Familial Hypocalciuric Hypercalcemia (FHH) is a rare and almost always asymptomatic condition, due to an autosomal dominant mutation of the calcium-sensing receptor gene. We report the case of a 61-year-old female with chronic hypercalcemia and joint pain. Clinical and biological data revealed chondrocalcinosis associated with FHH. Since primary hyperparathyroidism may mimic FHH, calcium to creatinine clearance ratio should be calculated in every case to avoid a wrong diagnosis and useless parathyroid surgery. The paucity of FFH complications, including chondrocalcinosis, makes their study difficult: additional studies are needed to clearly evaluate the link between FHH and chondrocalcinosis. © 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Familial Hypocalciuric Hypercalcemia (FHH), also known as Marx’s syndrome, was first documented in 1966 by Jackson and Boonstra and fully described in 1972 by Foley et al. It is a rare and benign condition–its prevalence is estimated at 1 in 78,000 people in West Scotland [1]. Genetic inheritance is autosomal dominant. It is characterized by an inactivating mutation of the calcium-sensing receptor (CaSR) gene. The CaSR is a protein-coupled receptor of 1078 amino acids, expressed in many tissues but mostly in parathyroid glands, kidneys and bones. So far, 139 inactivating mutations have been described [2]. CaSR senses extracellular calcium level to adjust urinary calcium level and parathyroid hormone (PTH) synthesis and excretion. Thus, a rise of calcium serum level leads to increased calcium urine excretion and decreased PTH synthesis [3]. In FHH, the inactivating mutation causes a loss of function of the CaSR and affects many tissues. Parathyroid cells become less sensitive to a rise in serum ionized calcium. Indeed, PTH secretion persists even if the calcium serum level is high and a higher calcium serum level is needed to suppress PTH secretion.
∗ Corresponding author. E-mail address: [email protected] (P. Guggenbuhl).
CaSR is expressed in kidneys in almost every part of the nephron. The inactivating mutation decreases sensitivity of kidney cells to serum and urine calcium levels. This leads to an enhanced tubular reabsorption of calcium and thereby reduces calcium urine excretion. Since creatinine clearance is not affected by the disease, calcium urine excretion can be easily evaluated using the calcium to creatinine clearance ratio (CCCR): CCCR = (Cau × Crs )/(Cas × Cru ). This ratio is a key diagnosis criterion if < 0.01. CaSR loss of function does not affect the balance between osteoclastic and osteoblastic function. There is no osteoclastic activation as observed in primary hyperparathyroidism (PHPT). That is why Bone Mineral Density (BMD) is most often normal in FHH in contrast to PHPT [4]. Furthermore, some physiopathological aspects of FHH remain unclear and other cells, such as osteocytes and lining cells, may be involved. Chondrocalcinosis (CC) is characterized by calcium pyrophosphate dehydrate crystal deposition in joints. It can be revealed by mono- or polyarthritis but can also be asymptomatic. While it is a common disease, its epidemiology is poorly known. Prevalence is higher with aging. According to the Framingham Osteoarthritis Study, knee radiological involvement is approximately 3% between 65 and 69 years of age while it rises up to 27% beyond 85 years of age [5]. Most CCs are idiopathic, but there are secondary forms mainly due to PHPT, hemochromatosis, hypomagnesemia, hypophosphatasia or familial diseases.
http://dx.doi.org/10.1016/j.jbspin.2014.08.007 1297-319X/© 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
L. Alix, P. Guggenbuhl / Joint Bone Spine 82 (2015) 60–62
Fig. 1. Meniscal calcifications in both knees.
FHH association with CC was first described by Health in 1989 [6]. To our knowledge, only one other case has been reported since [7].
61
Our patient was tested for a mutation of the CaSR gene: a missense mutation in the second exon of the CaSR gene was identified (c.157T > C; p.S53P), confirming the diagnosis of FHH. Additional research revealed that one of the patient’s sisters had a diagnosis of chronic hypercalcemia with hypocalciuria in 1992 (serum calcium level was at 2.8 mmol/L and CCCR 0.009) and that she has the same mutation of the CaSR gene. She also has a mutation of the seventh exon (c.2956G > T; p.A986S): this mutation is associated with hypercalcemia but is not related to FHH [2,8]. After a 6-year follow-up, polyarthralgia (especially of wrists and knees) remained but seemed to be less active. The patient had been successfully treated with acetaminophen and occasionally nefopam. Since colchicine was ineffective, it had been stopped. In the last assessment, hypercalcemia remained (2.78 mmol/L) without sign of acute hypercalcemia. PTH was still in the normal range, CCCR was 0.013. BMD was steady without antiresorptive drugs.
2. Case report
3. Discussion
We report the case of a 61-year-old female who was referred to our department to undergo clinical investigations concerning hypercalcemia associated with chronic polyarthralgia. She complained of joints pain that had been affecting wrists, knees, ankles and upper spine for ten years. She had several short accesses of joint pain (3–4 days) a year. She had no sign of acute hypercalcemia. She reported hypercalcemia in a brother, a sister, and her daughter. Physical examination was normal; there was no joint tenderness or swelling. Biological tests indicated mild hypercalcemia (2.75 mmol/L). Phosphatemia was normal (1.02 mmol/L), so was PTH level (29 pg/mL) while 25-OH Vitamine D was slightly lowered (23 ng/mL). PTH-related peptide and blood protein electrophoresis were both normal. CCCR was 0.017. Joint X-rays showed chondrocalcinosis of knees (Fig. 1), right wrist (Fig. 2) and pubic symphisis. Parathyroid ultrasound and scintigraphy were both normal. CT-scan revealed a 9 mm adrenal gland adenoma but did not report any ectopic parathyroid adenoma. DXA showed osteopenia (T-score at hip = –1.4 SD, femoral neck = –1.5 SD). Hypercalcemia was initially treated with an infusion of pamidronate (30 mg) and saline infusions. Joint pain was treated by colchicine (1 mg/day) and acetaminophen. Three months later, pain was unchanged. Hypercalcemia persisted (2.85 mmol/L) while PTH was still normal (36 pg/mL). A second perfusion of pamidronate 30 mg was administered to the patient. She also underwent a full screening in the department of endocrinology, including a pituitary MRI: it was concluded to a benign adrenal gland adenoma. There was no evidence of Multiple Endocrine Neoplasia (MEN).
FHH is a benign asymptomatic condition in most cases. Despite hypercalcemia, patients have a normal life expectancy. Very few complications had been described in FHH. Gallstones, pancreatitis and CC were the most common. In our case, there were no arguments for a secondary form of CC: ferritin level (56 ng/mL) and transferrin saturation (39%) were both normal, excluding hemochromatosis. Alkaline phosphatase (65 IU/L) and magnesemia were also normal (0.86 mmol/L), ruling out hypophosphatasia and hypomagnesemia. Furthermore, our patient was quite young when the first symptoms began (approximately 50 years old), as was the patient in the other reported case of CC associated with FHH (58 years old). Those relatively young ages go against idiopathic CC. It is, nevertheless, impossible to prove whether those diseases are really due to FHH and are not fortuitously associated. In addition, it is interesting to notice that clinical presentation was different since the other patient had recurrent arthritis while ours did not. The long period between first symptoms and diagnosis (10 years in our case, 20 years in Volpe’s) may demonstrate the lack of knowledge concerning FHH. Since FHH may mimic PHPT, the main challenge is to make the diagnosis of FHH, to avoid a parathyroidectomy which is not indicated as it does not cure the patient and as it may imply postoperative complications. In a recent review, Christensen notices that up to 23% of unnecessary parathyroid surgeries could be found in FHH [9]; 10% in Health’s study [6] and 9% in Marx’s [10]. That is why a 24 h urine sample should be performed in any case of PHPT suspicion to calculate the CCCR and to lead the physician to the diagnosis of FHH sparing parathyroid surgery. A CCCR < 0.01 is a strong argument for FHH and should lead to further genetic investigations to confirm the diagnosis. In PHPT, CCCR is below 0.01 in only 4% of cases [11]. A CCCR > 0.02 should exclude FHH. Between 0.01 and 0.02, diagnosis is uncertain. According to Christensen, the 0.01 cut-off is not satisfying: up to 35% of FHH patients (as our patient) have a CCCR between 0.01 and 0.02. This strategy has a sensitivity of 98% [9]. If there is no identified mutation (in up to 82% of cases), other genetic investigations are recommended if there is a familial history of hypercalcemia. Those patients should be screened for MEN: MEN1 (menin gene), MEN-2 (RET gene) and for hyperparathyroidism 2 (HRPT-2 gene). In the absence of familial history, parathyroid surgery must be discussed. It is important that imaging examinations are made by trained operators and that vitamin D and/or diuretic drugs are stopped 5 days before blood and urine samples collection. A 24 h urine sample is essential, since a spot urine sample has been proved not to be reliable enough [10,12].
Fig. 2. Calcification of right wrist ligament.
62
L. Alix, P. Guggenbuhl / Joint Bone Spine 82 (2015) 60–62
It is also crucial that FHH patients inform their families in order to diagnose FHH in the other members of the family to spare useless and costly investigations and prevent parathyroid surgery. The physician has a key role to play here. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Cetani F, Pardi E, Borsari S, et al. Two Italian kindreds with familial hypocalciuric hypercalcemia caused by loss-of-function mutations in the calcium-sensing receptor (CaR) gene: functional characterization of a novel CaR missense mutation. Clin Endocrinol (Oxf) 2003;58:199–206. [2] http://www.casrdb.mcgill.ca/. [3] Brown EM, MacLeod RJ. Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev 2001;81:239–97. [4] Abugassa S, Nordenstrom J, Jarhult J. Bone-mineral density in patients with familial hypocalciuric hypercalcaemia (FHH). Eur J Surg 1992;158:397–402.
[5] Felson DT, Naimark A, Anderson J, et al. The prevalence of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study. Arthritis Rheum 1987;30:914–8. [6] Heath III. H. Familial Benign (Hypocalciuric) Hypercalcemia: a troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am 1989;18:723–40. [7] Volpe A, Guerriero A, Marchetta A, et al. Familial hypocalciuric hypercalcemia revealed by chondrocalcinosis. Joint Bone Spine 2009;76:708–10. [8] Heath III H, Odelberg S, Jackson CE, et al. Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains. J Clin Endocrinol Metab 1996;81:1312–7. [9] Christensen S, Nissen P, Vestergaard P, et al. Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes 2011;18: 359–70. [10] Marx SJ, Stock JL, Attie MF, et al. Familial hypocalciuric hypercalcemia: recognition among patients referred after unsuccessful parathyroid exploration. Ann Intem Med 1980;92:351–6. [11] Christensen SE, Nissen PH, Vestergaard P, et al. Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods. Clin Endocrinol (Oxf) 2008;69:713–20. [12] Cegla J, Saroya S, McGowan B, et al. Is it time to replace the 24 h urine calcium: creatinine clearance ratio in the investigation of PTH-dependent hypercalcaemia. Endocr Abstr 2010;21:13.
![[Chondrocalcinosis revealing familial hypocalciuric hypercalcemia: about one observation].](/assets/img/hold.png)
