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ARTICLE IN PRESS+ModelEndocrinol Nutr. 2011;xxx(xx):xxx---xxxENDOCRINOLOGÍA Y NUTRICIÓNwww.elsevier.es/endoORIGINAL ARTICLEUsefulness of genetic tests in familial hypocalciuric hypercalcemiawith atypical clinical presentationH22845Ignacio Fernández Lópeza,∗, Ignacio Fernández Pe˜nab, María...  
ARTICLE IN PRESS+ModelEndocrinol Nutr. 2011;xxx(xx):xxx---xxxENDOCRINOLOGÍA Y NUTRICIÓNwww.elsevier.es/endoORIGINAL ARTICLEUsefulness of genetic tests in familial hypocalciuric hypercalcemiawith atypical clinical presentationH22845Ignacio Fernández Lópeza,∗, Ignacio Fernández Pe˜nab, María Victoria Cózar Leóna,María Mar Viloria Pe˜nasc, Guillermo Martínez De Pinillos Gordilloa,Mariana Tomé Fernández-Ladredaa, Santiago Duran GarcíaaaUnidad de Gestión Clínica, Endocrinología y Nutrición, Hospital Universitario Virgen de Valme, Sevilla, SpainbUnidad de Gestión Clínica, Endocrinología y Nutrición, Hospital Universitario Virgen Macarena, Sevilla, SpaincUnidad de Gestión Clínica, Laboratorio Clínico, Hospital Universitario Virgen de Valme, Sevilla, SpainReceived 25 January 2011; accepted 17 April 2011KEYWORDSFamilial hypocalciurichypercalcemia;Genetic tests;Clinical presentationAbstractObjectives: Biochemical tests related to calcium and phosphorus metabolism have traditionallybeen considered as a reliable tool to differentiate familial hypocalciuric hypercalcemia (FHH)from primary hyperparathyroidism (PHPT). However, diagnosis may sometimes be difficult evenfor experienced clinicians. Our objective was to assess the accuracy of diagnostic tests in FHHand the circumstances in which genetic studies are required.Patients and methods: A descriptive study was conducted of two families with hypercalcemiaand suspected atypical FHH. Urinary calcium excretion was measured in 24-h urine using dif-ferent tests (calcium excretion (CE), urinary calcium/creatinine clearance ratio (UCCR)), andserum PTH and 25-hydroxyvitamin D levels were tested. Index cases underwent genetic study.Results: One patient from the first family showed overt, persistent hypercalciuria with valuesmore consistent with PHPT than with FHH if we consider, as proposed by guidelines, a UCCRlower than 0.01 as diagnostic of FHH and a value higher than 0.02 as diagnostic of PHPT. Theindex case of the second family underwent surgery for a parathyroid adenoma. Both cases hada mutation c. 164C>T (Pro55Leu) in exon 2 in heterozygosis.Conclusions: According to current clinical guidelines, definitive diagnosis of FHH requiresgenetic confirmation, which allowed in our case for detection of two families with FHH and atyp-ical clinical presentations. We think that rational use of genetic tests may avoid unnecessarysurgery and excess monitoring costs.© 2011 SEEN. Published by Elsevier España, S.L. All rights reserved.H22845Please cite this article as: Fernández López I, et al. Utilidad del estudio genético en la hipercalcemia hipocalciúrica familiaren familias con presentaciones clínicas atípicas. Endocrinol Nutr. 2011;58:325---30.∗Corresponding author.E-mail address: idomingof@ono.com (I. Fernández López).2173-5093/$ – see front matter © 2011 SEEN. Published by Elsevier España, S.L. All rights reserved.ENDOEN-224; No. of Pages 6ARTICLE IN PRESS+Model2 I. Fernández López et al.PALABRAS CLAVEHipercalcemiahipocalciúricafamiliar;Estudio genético;PresentacionesUtilidad del estudio genético en la hipercalcemia hipocalciúrica familiar en familiascon presentaciones clínicas atípicasResumenObjetivos: Tradicionalmente se ha pensado que las pruebas bioquímicas del metabolismofosfocálcico permiten diferenciar el hiperparatiroidismo primario (HPT1) y la hipercalcemiahipocalciúrica familiar (HHF) pero hay casos de difícil diagnóstico incluso para clínicos experi- del realizado con el si consideramos,el exón definitivo permitido intervenciones ElsevierIntroductionFamilialoffices.inantdiseases2tumorhypocalciuricfiveimplicationsnosticarerequiregeneaffectphenotypegosiswhichthephenotypicFHH.berwhichcalciumandpresencehypercalcemia,ically(urinary0.01),elevatederedclínicasmentados.Nos planteamos como objetivocomo la correcta indicaciónPacientes y métodos: Hemosy sospecha de HHF de característicasEn orina de 24 h hemos valoradocalcio [CE], cociente calcio/creatininade creatinina [CCCR]), juntolos casos índices se les realizóResultados: Una paciente presentódantes con HPT1 que de HHFcomo indicativo de HHF y superiorextirpó un adenoma de paratiroides.c. 164C>T (p.Pro55Leu) en Conclusiones: El diagnósticomación genética, lo cual hacaracterísticas clínicas atípicas.sospecha de HFF puede evitarmonitorización.© 2011 SEEN. Publicado por hypercalcemia is not uncommon in endocrinology It is a hereditary disorder with an autosomal dom- transmission in most cases1,2covering a spectrum of including multiple endocrine neoplasia type 1 and (MEN 1 and 2), hyperparathyroidism associated to jaw, isolated familial hyperparathyroidism, and familial hypercalcemia (FHH). Differentiation of the syndromes is sometimes difficult, but has profound for the patient and his/her family.Availability of specific genetic tests has improved diag- accuracy and simplified monitoring, but these tests costly and often not easily accessible, and therefore a rational use.Inactivating mutations in the calcium-sensing receptor (CaSR), located in the long arm of chromosome 3, may a single allele (heterozygosis), which results in the characteristic of FHH, or both alleles (homozy- or compound heterozygosis if no consanguinity exists), leads to severe neonatal hyperparathyroidism, so that grade of gene defect accounts for the great disparity in presentation.3Some 200 different mutations4have been reported in The end result of such mutations is a decreased num- of functional receptors in parathyroid cells and kidney, makes them partially resistant to calcium, so that high levels are required to decrease PTH and calcium magnesium are reabsorbed in the kidney even in the of hypercalcemia. FHH therefore causes persistenttoreportedceptibilityconditionissurgeryreceptorcalciuria,havePThisgeographicwhichandpresencechemicalmembers,andof evaluar la validez de las pruebas diagnósticas de la HHF así estudio genético. un estudio descriptivo de 2 familias con hipercalcemia atípicas. los índices de excreción urinaria de calcio (eliminación de [CR] y cociente aclaramiento de calcio/aclaramiento las concentraciones séricas de PTH y 25 hidroxivitamina D. A estudio genético. hipercalciuria franca y persistente con valores más concor- como proponen las guías, un CCCR inferior a 0,01 a 0,02 como HPT1. Al caso índice de la segunda familia se le En ambos casos índice, encontramos la misma mutación 2 en heterocigosis descrita como responsable de HHF. de HHF en las guías clínicas actuales requiere confir- en nuestro caso la detección de 2 familias con HHF y En nuestra opinión el uso racional de estas pruebas ante la quirúrgicas innecesarias y gastos excesivos en su España, S.L. Todos los derechos reservados. hypocalciuria which is either absolute (typ- less than 200 mg/day) or relative to plasma calcium calcium/creatinine clearance ratio [UCCR] less than and normal PTH levels, although 20% of patients have PTH levels.5,6FHH is a disorder which is consid- to be benign and asymptomatic and does not appear shorten life expectancy, but chondrocalcinosis has been in some adults and may confer an increased sus- to pancreatitis.7It is important to distinguish this from primary hyperparathyroidism (PHPT), which usually easy in the typical cases of both conditions because is unnecessary and ineffective in FHH.The clinical spectrum of mutations in the calcium-sensing is being widened with the genetic study, and hyper- stones8and, exceptionally, parathyroid adenoma been reported in patients with FHH.9atients and methods was a descriptive study of two families from the same area but with no common known family history had shown hypercalcemia during years of follow-up in which a genetic study had recently confirmed the of FHH, despite their discordant clinical and bio- data.The index cases of the first family, with four affected there was a 35-year-old woman 54.4 kg in weight 158 cm in height and with a body mass index (BMI) 21 kg/m2in whom laboratory tests performed for aARTICLE IN PRESS+ModelUsefulness of genetic tests in familial hypocalciuric hypercalcemia 3headache detected increased calcium levels (11.1 mg/dL),slightly decreased phosphorus levels (2.4 mg/dL), and nor-mal magnesium and creatinine levels. Other test resultsincluded 24-h urinary calcium of 272 mg, tubular phos-phate reabsorption (TPR) of 70%, urinary calcium/creatinineclearance ratio (UCCR) of 0.0137, elevated intact PTHlevels (110 pg/mL), and 25-hydroxyvitamin D deficiency(24.8 nmol/L). parathyroid ultrasonography and a Tc-(Ensembl: ENSG00000036828), coding regions of exons 2,3, 4, 5, 6, and 7 were amplified by PCR using flank-ing primers (http://frodo.wi.mit.edu/primer3/ was usedfor primer design). PCR products were sequenced usingthe BigDye Terminator v3.1 Cycle Sequencing Kit (AppliedBiosystems, Foster City, CA) and were purified using the Mil-lipore system (96-well plates Multiscreen PCRu96 & Montageseq96). Products were then analyzed in an ABI Prism GeneticAnalyzerResultsOfUCCR),offorwhichsorbedvalueinfamilyfrank,considered.diateFHH.associatedmodulatestionalincreasedhypocalcemiaaboveandTherenalhadphosphorusUCCRofofandwithpathologicalhypercalcemialevelswassuggestpassedstudythereportedcalciumtohypocalciuriaels.resectedsestamibi scan showed no enlargement of parathyroidglands, adenoma, or ectopic tumors. Abdominal ultrasonog-raphy was normal, as was bone densitometry of the spine,showing a T score of −0.02 and a Z score of 0.50.Family study revealed asymptomatic hypercalcemia inthe 70-year-old father of the woman and in her two sons,aged 18 and 12 years. Soon after diagnosis, the eldestson experienced repeated episodes of renal colic and grosshematuria but passed no stones, which were not visiblein standard abdominal X-rays. He attended the emergencyroom of our hospital for that reason in 2004, 2008, and 2010.In the second family, the index case was a 39-year-oldmale 92 kg in weight and 173 cm in height (BMI, 30.7 kg/m2)in whom hypercalcemia was discovered during work-up forhyperlipidemia. Further investigation revealed hypercal-cemia in two of four brothers, including the index case,and also in the mother and one uncle. Initial laboratorytests showed 11.7 mg/dL of calcium, 2.74 mg/dL of phos-phorus, and 2.19 mg/dL of magnesium. Urinary calciumlevels were 82 mg/24 h, UCCR 0.003, urinary phosphate lev-els 1.254 mg/24 h, and TPR, 80%. Intact PTH was elevated(72 pg/mL) and 25-hydroxyvitamin D levels were decreased(40 nmol/L [normal range, 50---250]). Bone densitometryshowed spine osteopenia (T score −1.30 and Z score −1.20).Thyroid ultrasonography was normal, but a Tc-sestamibiscan showed pathological retention of the radiotracer in thelower portion of left thyroid lobe consistent with a parathy-roid adenoma in the left inferior parathyroid gland.Calcium phosphorus, magnesium, alkaline phosphatase,and creatinine were measured in fasting conditions using aCobas c711 Hitachi analyzer (Roche Diagnostics).Calcium and phosphate levels and TPR were tested in24-h urine while patients were taking an unrestricted diet,and diuretic use by patients was ruled out. The three mostcommonly used indices of urinary calcium excretion wereassessed, defining hypercalciuria as calcium excretion (CE)greater than 4 mg/kg/24 h or 240 mg in females and 300 mgin males or a calcium/creatinine ratio (CR) greater than0.2 mg/kg. A UCCR (calcium in 24-h urine × serum creati-nine/serum calcium × urinary creatinine) less than 0.01 wasconsidered indicative of hypocalciuria.Chemoluminescence (Inmulite 2000, Siemens) was usedto measure intact PTH (normal range, 11---67 pg/mL) and25-hydroxyvitamin D (normal range, 50---250 nmol/L) levels.Vitamin levels less than 25 nmol/L were considered indica-tive of severe deficiency, while levels ranging from 25 to50 nmol/L and from 50 to 75 nmol/L were, respectivelydefined as insufficient and suboptimal in Andalusia10).Index cases of each family were requested to consent fora molecular genetic study for the calcium receptor gene,which was performed at the department of biochemistry andmolecular genetics of Hospital Clínico in Barcelona.DNA was extracted from white blood cells from wholeblood using QIAmp DNA (QIAGEN). For CaSR gene analysis 3130.xl (Applied Biosystems). the three renal calcium excretion indices (CE, CR, and UCCR is considered to be the index of choice because its better discriminating power. Guidelines recommend UCCR a cut-off point less than 0.01 for diagnosis of FHH, means that more than 99% of filtered calcium is reab- despite the presence of hypercalcemia, and a cut-off higher than 0.02 for PHPT diagnosis.Table 1 shows the basic descriptive laboratory variables the eight years of follow-up of the index case of the first.As shown by 24-h calcium elimination, our patient had persistent hypercalciuria over time if CE and CR are Assessment of UCCR results revealed interme- values, and some clearly suggesting PHPT rather thanThese high urinary calcium levels also coincide with an deficiency of vitamin D, whose concentration the severity of the condition by causing an addi- decrease in urinary calcium and often justifying the PTH levels seen in FHH and found in our patient.Unlike her, her two sons have shown hypocalciuric since 1996, with UCCR below or very slightly 0.01. The youngest son has remained symptom-free with normal 25-hydroxyvitamin D levels (80 nmol/L). eldest son experienced in 2005 three episodes of colic requiring treatment at the emergency room. He at the time a plasma calcium level of 11.7 mg/dL, a level of 3.17 mg/dL, 24-h urine CE of 248 mg, of 0.0123, an inappropriately elevated PTH level 84 pg/mL, and a decreased 25-hydroxyvitamin D value 49 nmol/L. Abdominal and cervical ultrasonography Tc-sestamibi scan were normal. Exploratory surgery subtotal parathyroidectomy was performed, but no changes were found in parathyroid glands, and persisted after surgery. Oxalate and citrate in 24-h urine were normal, but uric acid excretion persistently elevated (up to 1542 mg/24 h), which may the presence of uric stones, but patient has not to date stones amenable to analysis.Because of the discordant data in this family, genetic of the index case was performed in 2010, revealing c. 164C>T (Pro55Leu) mutation in exon 2, which has been to be responsible for FHH.In the index case of the second family, patient age, concentrations, osteopenia, and scan uptake led also perform exploratory surgery in the neck, with being explained by his low vitamin D lev- An adenoma in the left inferior parathyroid gland was at surgery, and PTH levels decreased from 72 pg/mLARTICLE IN PRESS+Model4 I. Fernández López et al.Table 1 Basic descriptive laboratory variables in the index case of the first family.Years of follow-up 1 2 3 4 5 6 7 8Calcium (mg/(dL) 11.1 10.8 10.6 11.7 10.4 11.5 11.1 11.8Phosphorus (mg/(dL) 2.4 3.0 2.11 2.62 2.46 2.69 2.79 2.8Creatinine (mg/(dL) 0.86 0.78 0.69 0.60 0.60 0.65 0.57 0.60Magnesium (mg/dL) 2.12 1.99 2.11 2.01 2.20 2.40 2.30 2.4043391duringtotal9.8calcemiaannualvitaminupmagnesium120symptom-freeduringadenoma,ac.reportedDiscussionInfindinggeneparathyroidismmoretwoFHH.twoconsistingofpatterniliesWhenativeineffectiveshouldevenmentgivesindexFHHfamiliesdeinpresenceetc.)offalseiciansTheystantialposehavenormalPTHguidelines0.01sisstudythreeofexcretionlessespeciallycurrentlysideredhypercalciurianosticPHPTtreated,lesshasfirstThisvalue,to0.020,thosePTH (pg/mL) 110 81 Calcium in 24-h urine (mg/24 h) 272 240 Calcium/creatinine ratio in 24-h urine 0.18 0.27 UCCR 0.014 0.019 UCCR: urinary calcium/creatinine clearance ratio. surgery to 47 pg/mL after the procedure. Although calcium level normalized the day after surgery to mg/dL, patient continued to show hypocalciuric hyper- (UCCR less than 0.01 at all times) at subsequent follow-up visits to our clinic despite normalization of D levels after treatment. Results at the last follow- included: calcium 11.5 mg/dL, phosphorus 1.96 mg/dL, 2.3 mg/dL, UCCR 0.009, 25-hydroxyvitamin D nmol/L, and PTH 34.8 pg/mL.All other three members of the family remained and had UCCR values also lower than 0.01 the years of follow-up.Based on discordant history data, surgery for parathyroid and family data of hypocalciuric hypercalcemia, genetic study was recently requested and also showed the 164C>T (Pro55Leu) mutation in exon 2 in heterozygosis to be responsible for FHH. recent years, availability of genetic tests has allowed for families with heterozygous mutations in the CaSR which show clinical features characteristic of hyper- such as hypercalciuria, kidney stones and, rarely, parathyroid adenoma. We monitored for years families, with eight affected members, with suspected This was recently confirmed by genetic testing, but of the patients were found to have a discordant course, of sustained hypercalciuric hypercalcemia in one them and parathyroid adenoma in the other.Familial hypercalcemia follows an autosomal dominant of inheritance, and is therefore diagnosed in fam- with several affected members, many of them young. patients have asymptomatic hypercalcemia with rel- hypocalciuria, especially if there is a history of parathyroid surgery, urinary and plasma levels be investigated in several generations of relatives if they are apparently unaffected. Calcium measure- in blood and urine from three members of a family less false positive results than a genetic study in an case. If an individual subject has no affected relatives, is highly unlikely,11but cannot be ruled out because with recessive inheritance have been reported,11or novo mutation may occur. No CaSR mutations are found up to 30% of families, which may be due in some cases totionsbecausetionandwithelsthesein 78 61 49 62 93 550 323 502 405 3320.57 0.38 0.26 0.39 0.35 0.330.036 0.019 0.015 0.022 0.018 0.017 of mutations in other regions (promoter, introns, or implication of other different genes.The fact that genetic tests are not indispensable because the benign nature of the condition, their cost, their high negative rate, and their difficult accessibility for clin- until recently have limited their routine use in FHH. may, however, prevent unnecessary surgery and sub- expenses in doubtful cases.12Most cases of FHH and familial PHPT do not usually problems in differential diagnosis, but both diseases atypical presentations difficult to differentiate. Thus, PTH levels are found in 10% of PHPT, and high levels are seen in 15---20% of patients with FHH. The12propose cut-off points for UCCR of less than for diagnosis of FHH and more than 0.02 for diagno- of PHPT, which are widely quoted and accepted.13A14recently assessed the discriminating power of the renal indices and established an optimum cut-off point 0.0115, but there may be overlapping in urinary calcium between the two conditions.A decreased renal calcium excretion, with a UCCR even than 0.001, may be found in some patients with PHPT, if they also have vitamin D deficiency, which is so common in Spain and Andalusia as to be con- an epidemic,15---17and patients with FHH may have or, more rarely, stones,1,8which causes diag- errors even in the hands of experienced clinicians.Twenty percent of cases of FHH and up to 12% of those of would be inadequately classified and potentially mis- even if the cut-off point for UCCR is increased from than 0.01 to 0.0115. A two-step diagnostic approach therefore been suggested13for doubtful cases. UCCR is determined using a cut-off value of less than 0.020. excludes two thirds of PHPTs, which will have a higher and will include 98% of FHHs. The next step would be determine the CaSR gene in families with UCCR less than which separates patients with mutations (FHH) from with mutations (PHPT).A potential cause of error is not assessing concentra- of vitamin D, which is indispensable in these patients its deficiency causes decreased intestinal absorp- and renal excretion of calcium, increased PTH levels, inactivation of the calcium-sensing receptor.18Patients PHPT appear to have lower 25-hydroxyvitamin D lev- as compared to controls, and renal calcium excretion in patients positively correlates to these levels, reaching patients with deficiency levels typical of FHH.10,19ARTICLE IN PRESS+ModelUsefulness of genetic tests in familial hypocalciuric hypercalcemia 5On the other hand, it should be noted that intensity of theCaSR gene mutation is variable and conditions the extent ofPTH secretion, tubular calcium reabsorption, and calcemiain an individual patient.Our two index cases from both families with FHH haddecreased levels of 25-hydroxyvitamin D. In one of them,vitamin D replacement therapy decreased PTH levels but,as reported in patients with FHH,20did not change renalConflicts of interestThe authors state that they have no conflicts of interest.Referencescalcium excretion, which continued to be very low (UCCRless than 0.01). Absence of a sustained increase in PTH inpatients with FHH contributes to its usually benign courseand to the absence of bone involvement.21One of the patients had sustained hypercalciuria, despitethe associated vitamin D deficiency, with UCCR values higherthan 0.02 for years of follow-up, which is exceptional. One ofher sons had repeated renal colic associated to hypocalciuriaand high uric acid levels in urine.At least 9% of cases with persistent hypercalcemia fol-lowing ineffective surgery22are patients not diagnosed withFHH. Pathological examination of parathyroid glands showeda slight enlargement or mild hyperplasia, but no nodular-ity is usually found. We report a genetically proven case ofFHH in which a TC-sestamibi scan revealed a left inferiorparathyroid adenoma which was confirmed at surgery. Thistechnique has an 85---100% sensitivity for localizing adenomabefore surgery, and a specificity close to 100% if there is noconcurrent thyroid involvement, as occurred in our case.23It is unknown whether FHH is a risk factor24for sub-sequent development of PHPT. Expression of CaSR proteinis often reduced in adenomas from patients with PHPT.24One may therefore speculate that total or partial loss ofreceptor function may stimulate proliferation of parathyroidcells. Association of homozygous inactivating CaSR muta-tions to PHPT due to multiple parathyroid adenomas andsevere persistent hypercalcemia after surgery has recentlybeen reported, suggesting that loss of receptor functionmay occasionally induce PHPT in adults.25Both diseases mayrarely occur together. A search in Medline found that fourcases of parathyroid adenoma in patients with geneticallyproven FHH have been reported in the past 10 years.8,9,26,27This could be a simple coincidence, as PHPT is a commondisease, but presence of parathyroid adenomas in differentgenerations of one of our families does not appear to be dueto chance.925-Hydroxyvitamin D deficiency in PHPT is associatedto more aggressive evolution with greater bone involve-ment, and new guidelines28therefore recommend vitamin Dreplacement.For some authors, vitamin D deficiency may have a role indevelopment of parathyroid adenoma, and they suggest thatchronic deficiency accelerates adenoma growth9,19and thatvitamin D supplementation may reverse this process by act-ing upon the normal allele of FHH patients, but conflictingdata are available.29,30To sum up, availability of genetic studies is allowing forexpanding the clinical spectrum of FHH. For current clinicalguidelines,11final diagnosis of FHH requires genetic test-ing. We analyzed the current genetic screening protocols inpatients with suspected FHH for rational use. A genetic testfor the CaSR mutation in atypical cases, such as the onesreported here, may prevent unnecessary surgery and, in ouropinion, excess follow-up costs.1. Warner J, Epstein M, Sweet A, Singh D, Burgess J, Stranks S,et al. Genetic testing in familial isolated hyperparathyroidism:unexpected results and their implications. J Med Genet.2004;41:155---60.2. Lietman SA, Tenembaum-Rakover Y, Shing T, Yi-Chi W,de-Ming Y, Ding C, et al. A novel loss-of-function mutation,Gln459Arg, of the calcium-sensing receptor gene associatedwith apparent autosomal recessive inheritance of famil-ial hypocalciuric hipercalcemia. J Clin Endocrinol Metab.2009;94:4372---9.3. Pollak MR, Chou YH, Marx SJ, Steinmann B, Cole DE, Brandi ML,et al. Familial hypocalciuric hypercalcemia and neonatalsevere hyperparathyroidism. 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Grey A, Lucas J, Horne A, Gamble G, Davidson JS, Reid IA.Vitamin D repletion in patients with primary hyperparathy-roidism and coexistent vitamin D insufficiency. J Clin EndocrinolMetab. 2005;90:2122---6.21. Christensen SE, Nissen PH, Vestergaard P, Heickendorff L,Renjmark L, Brixen K, et al. Skeletal consequences of familialhypocalciuric hypocalcemic vs. primary hyperparathyroidism.Clin Endocrinol (Oxf). 2009;71:798---807.22. Marx SJ, Stock JL, Attie MF, Downs Jr RW, Gardner DG,Brown EM, et al. Familial hypocalciuric hypercalcemia:recognition among patients referred after unsuccess-ful parathyroid exploration. Ann Intern Med. 1980;92:351---6.23. Torres Vela E, Quesada Charneco M. Diagnóstico de local-ización del hiperparatiroidismo primario. Endocrinol Nutr.2006;53:453---7.24. Kifor FD, Moore Jr P, Wang M, Goldstein P, Vassilev I,Kifor SC, et al. Reduced immunostaining for the extracellularCa2+-sensing receptor in primary and uremic secondary hyper-parathyroidism. 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Usefulness of genetic tests in familial hypocalciuric hypercalcemia

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