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Endocrine Care |
Service de Pédiatrie (A.L.), Centre Hospitalier Universitaire, 87042 Limoges, France; Endocrine-Hypertension Division, Department of Medicine (M.B., Z.Z., Y.J., E.M.B.), Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts 02115; Service de Biochimie Médicale, AP-HP (J.-P.L.), Hôpital Pitié-Salpétrière, 75013 Paris, France; Service de Biochimie (M.R.), Faculté de Médecine, 87025 Limoges, France; Département de Génétique et de Reproduction (M.-L.K.), Centre Hospitalier Universitaire, 14031 Caen, France; and Unité Centre de la Recherche Scientifique, Unité Propre de Recherche 1524 (M.G.), Hôpital Saint Vincent de Paul, 75014 Paris, France
Address all correspondence and requests for reprints to: Dr. Anne Lienhardt, Département de Pédiatrie Médicale, Center Hospitalier Universitaire Dupuytren, 2 avenue Martin Luther King, 87042 Limoges Cedex, France. E-mail: anne.lienhardt{at}unilim.fr
Abstract
Activating mutations of the calcium-sensing receptor (CaR) can cause isolated hypoparathyroidism. Treatment of hypocalcemia in these patients remains to be optimized, because the use of 1-hydroxylated vitamin D3 derivatives can cause hypercalciuria and nephrocalcinosis.
We identified activating CaR mutations in 8 (42%) of 19 unrelated probands with isolated hypoparathyroidism. The severity of hypocalcemic symptoms at diagnosis was independent of age, mutation type, or mode of inheritance but was related to the degree of hypocalcemia; serum Ca was 1.97 ± 0.08, 1.82 ± 0.14, and 1.54 ± 0.22 mmol/liter, respectively, in asymptomatic (n = 7), mildly symptomatic (n = 8), and severely symptomatic patients (n = 6). Hypocalcemia segregated with the CaR mutation, but no phenotype-genotype relationships were identified. Fourteen patients received regular 1-hydroxylated vitamin D3 treatment (mean duration, 7.2 ± 4.9 yr). Nine had hypercalciuric episodes, which were associated with nephrocalcinosis in eight cases. Serum Ca during treatment predicted hypercalciuria and nephrocalcinosis poorly, because either or both of the latter could develop in hypocalcemic patients.
Thus, mutational analysis of the CaR gene should be considered early in the work-up of isolated hypoparathyroidism. Treatment options should be weighed carefully in patients with serum Ca below 1.95 mmol/liter. The risk of nephrocalcinosis during treatment can be minimized by carefully monitoring urinary Ca excretion.
HYPOPARATHYROIDISM IS AN abnormality of Ca metabolism characterized by low serum levels of PTH despite hypocalcemia. It can occur as an isolated abnormality or in a familial setting, sometimes as a component of genetic syndromes involving multiple endocrine glands (1). Although most cases of isolated hypoparathyroidism are sporadic, some exhibit X-linked, autosomal recessive or autosomal dominant modes of inheritance (1). Linkage analysis performed in large families with autosomal dominant hypoparathyroidism mapped a candidate gene to a chromosome 3q13 locus, corresponding to the region known to harbor the gene encoding the human Ca-sensing receptor (CaR) (2, 3, 4). The CaR belongs to family C of the superfamily of G protein-coupled receptors. The bovine CaR was initially cloned in 1993 (5), and the human homologue of the receptor was isolated in 1995 (6). Heterozygous activating mutations of the CaR gene, by resetting parathyroid and kidney so as to maintain hypocalcemia, cause sporadic or autosomal dominant forms of isolated hypoparathyroidism (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23). The latter has been termed autosomal dominant hypocalcemia (24). The prevalence of activating mutations of the CaR as a cause of isolated hypoparathyroidism is unknown, making it difficult to identity those patients with hypoparathyroidism in whom mutational analysis is warranted. Furthermore, patients reported in the literature often develop nephrocalcinosis. It is important, therefore, to determine the optimal mode of treatment for this condition, which minimizes the risk of hypercalciuria and resultant complications, particularly nephrocalcinosis and impaired renal function (9).
In an attempt to clarify these aspects of the diagnosis and treatment of patients with activating mutations of the CaR, a large collaborative study was undertaken. Eight different missense mutations and a deletion within the CaR gene were identified in a cohort of 19 unrelated index cases presenting with isolated hypoparathyroidism. Family screening in the 8 families harboring activating mutations of the CaR gene revealed a total of 21 affected patients. The presence of hypocalcemia segregated with the mutated CaR gene in all cases, but no phenotype-genotype relationships were identified. Clinical and biochemical data that were recorded at diagnosis and during follow-up were analyzed in this large homogeneous population of patients with gain-of-function mutations in the CaR gene. On the basis of the results of this analysis, we propose a strategy for managing the hypocalcemia in this disorder that minimizes the risk not only of severe clinical symptoms but also of nephrocalcinosis and other renal complications.
Patients and Methods
Patients
Nineteen unrelated index cases with hypoparathyroidism were included in this study (9 males and 10 females). They were selected on the basis of having hypocalcemia due to isolated hypoparathyroidism. All presented with symptomatic hypocalcemia (mean ± SD, 1.53 ± 0.34 mmol/liter; range, 0.93–2.18; normal values, 2.20–2.60) at the time of diagnosis, which ranged from the immediate postnatal period to the age of 52. All had inappropriately low serum PTH levels when measured with either assays for intact PTH (7.3 ± 4.9 pg/ml; range, 0–16; normal values, 10–60; n = 14) or those recognizing the C-terminal or mid-region of the PTH molecule (n = 5). The entire coding sequence of the CaR gene was evaluated as described in the next section. When a mutation in the CaR gene was identified, a molecular survey of the respective families was performed. Informed consent was obtained from all subjects according to the guidelines of the local consultative committee for the protection of human subjects participating in biomedical research.
Molecular evaluation of the CaR gene
PCR amplification of genomic DNA and sequence analysis. Genomic DNA was extracted from leukocytes using a proteinase K-phenol-chloroform procedure (25). Exons 2–7 of the CaR gene, encompassing the entire coding sequence, were amplified using the PCR with previously reported primers (19, 26, 27). PCR products were electrophoresed on 1% agarose gels, visualized with ethidium bromide, and then purified on Microcon-100 columns (AMICON, Beverly, MA). Both strands of the purified products were directly sequenced using the Amplitaq dye Terminator Cycle Sequencing kit and an ABI PRISM 377 DNA sequencer (Perkin-Elmer Corp., Roissy, France).
Segregation analysis was conducted using either restriction analysis when the mutation in the CaR gene destroyed or introduced a restriction site or direct sequencing of PCR products.
In vitro expression. Biological activities of the mutated receptors were studied using in vitro expression as previously described (28). Briefly, the various mutations that had been identified were engineered into a reconstructed wild-type (WT) human CaR cDNA by PCR. The WT-CaR and the respective mutant CaRs were then transiently expressed in human embryonic kidney (HEK293) cells. The transfected cells were exposed to increasing extracellular Ca concentrations; changes in the cytosolic Ca concentration of fura-2-loaded cells and analysis of the resultant data were performed as before (29). To mimic the heterozygous state in vivo, cotransfections were performed with the cDNAs encoding the WT-CaR and a given mutant CaR.
Clinical study
Initial clinical presentation and outcome. All index patients harboring activating mutations of the CaR (n = 8) and other members of their families shown by family screening to carry a mutation (n = 13) were included in this long-term retrospective analysis. All available clinical and biochemical data recorded at the time of diagnosis and during follow-up were analyzed in close collaboration with the patients’ medical practitioners. Some patients underwent renal ultrasound and measurements of serum PTH and of serum and urinary Ca concentrations after they were recognized to harbor an activating mutation of the CaR.
Statistical analyses. Results are presented as mean ± SD. Unpaired t test or ANOVA was used as appropriate to analyze the data. Statistical significance was assigned at a P value less than 0.05.
Results
Molecular findings
DNA sequencing. A mutation in the CaR gene was identified in 8
(4 males and 4 females) of the 19 index cases (42%). Seven of the
mutations are missense mutations involving the extracellular domain of
the receptor (Leu125Pro, Glu127Lys, Cys129Phe, Pro221Leu), the
transmembrane (TM) domains (Phe788Cys in TM5, Ala843Glu in TM7), or the
third intracellular loop (Glu799Lys). The eighth mutation is a large
deletion from Ser895 to Val1075 within
the intracellular carboxyl-terminal (C-) tail of the CaR (Table 1
and
Fig. 1), which has been reported
previously (19). All of the patients carried a single
mutant allele, except for one (8-I1) who was homozygous for the
deletion within the C-tail of the receptor (19).
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). When the
cDNAs encoding five of the mutant receptors were each cotransfected
with the WT-CaR cDNA, the resultant EC50 values
showed a persistent gain-of-function (Table 1). One mutant receptor
(Ala843Glu) exhibited equivalent biological activities at all levels of
extracellular Ca that were tested. Family survey and segregation analysis
A molecular survey of the 8 index patients’ families was
undertaken; it included 49 family members (Fig. 2). Segregation analysis showed the
presence of a heterozygous CaR gene mutation in 13 of them, including 9
males and 4 females. In four families (numbers 1, 2, 5, 7), both living
parents of the index patient could be studied; assuming biological
paternity, the CaR mutations occurred de novo in these
families, because the parents did not carry the respective mutations.
In the other families, a CaR mutation was found in several generations
with an autosomal dominant pattern of inheritance. In three of these
families (families 3, 6, 8), it was not possible to determine whether
probands had de novo or inherited CaR mutations, because one
or both parents were deceased.
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Clinical and biochemical findings
Age at diagnosis of index patients. The four index patients
with de novo mutations (families 1, 2, 5, 7) were diagnosed
during their first several months of life
because of severe hypocalcemic symptoms
requiring Ca infusion (Table 2). In contrast, hypocalcemia was
only diagnosed at the ages of 4.3, 23, 50, and 52 yr in the other four
index cases.
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Although several values for serum Ca concentration were available in
every case, we chose to analyze those that were temporally matched with
measurements of serum PTH. At the time of diagnosis, the mean serum Ca
concentrations were significantly different (ANOVA, P =
0.0005) in the three groups of patients with no, mild, or severe
symptoms, which were 1.97 ± 0.08 mmol/liter (range, 1.87–2.08),
1.82 ± 0.14 mmol/liter (range, 1.56–1.97), and 1.54 ± 0.22
mmol/liter (range, 1.22–1.77), respectively (Fig. 3). Neither the severity of the clinical
presentation nor the serum Ca concentration was related to the affected
patients’ age or type of mutation. Moreover, there was considerable
variability in the clinical phenotypes and baseline
(i.e. untreated) levels of serum Ca in
affected members from the same family.
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). Most of the 13
patients in whom data were available for urinary Ca excretion had
relative hypercalciuria (i.e. values that were
inappropriately normal or at the upper limit of normal, given the
patients’ coexistent hypocalcemia), but four experienced absolute
hypercalciuria (Table 2).
Clinical outcome. Seven of the 21 hypocalcemic patients were
not compliant with treatment or refused follow-up and treatment after
their hypocalcemia had been diagnosed, arguing that they were well. The
14 other patients were followed on a
regular basis and received daily oral doses of 1-hydroxylated
analogues of vitamin D3 [1
(OH)D3] for a
mean duration of 7.2 ± 4.9 yr (Tables 3 and 4). When analyzed together,
treatment significantly improved their serum Ca levels (2.13 ±
0.39 vs. 1.71 ± 0.24 mmol/liter before treatment,
P < 0.0001). There was no significant decrease in
serum intact PTH levels (8.5 ± 3.6 vs. 8.9
± 3.3 pg/ml in the eight patients in whom serum intact PTH levels were
available before and during treatment).
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(OH)D3 produced rapid disappearance of the
symptoms of hypocalcemia and significantly increased serum Ca
concentrations in the six patients with severe symptoms at the time of
diagnosis (Fig. 4 and Table 3). During
treatment, the patients receiving the highest dose of 1
(OH)D3 (4 µg/d) experienced episodes of severe
hypercalcemia (up to 4.10 mmol/liter), and two of the five patients
receiving lower doses (up to 2.5 µg/d) exhibited periods of mild to
moderate hypercalcemia (up to 3.20 mmol/liter). Five of these patients
had permanent or transient hypercalciuria, and renal ultrasound
revealed nephrocalcinosis in four of them. Reduction of the dosage of
vitamin D led to disappearance of the renal calcifications in one
patient, as assessed by ultrasound.
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(OH)D3 relieved
hypocalcemic symptoms in the groups of patients with mild or no
symptoms at diagnosis but did not produce any significant increase in
serum Ca concentration (Fig. 4). During treatment, mild hypercalcemic
episodes occurred in three of eight patients receiving 1
(OH)D3 dosages of 2–4 µg/d (Table 4).
Permanent or prolonged hypercalciuric episodes and nephrocalcinosis
were noted in four patients. None of the patients had severely impaired
renal function.
Independent of the clinical presentation at diagnosis, nephrocalcinosis
was observed in all eight patients with clearly elevated urinary Ca
excretion during treatment, although renal ultrasound tests had not
been performed before the initiation of treatment. The occurrence of
nephrocalcinosis was not closely related to the level of serum Ca,
because it was present in most (n = 5) but not all patients
(n = 1) with hypercalcemic episodes. Renal calcifications were
also noted by ultrasound in patients (e.g. 3II5 and 5II1)
who had never experienced hypercalcemia and whose serum Ca
concentrations had been maintained below the normal range during most
of their follow-up (Tables 3 and 4 and Fig. 5).
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The CaR is a cell surface ion-sensing receptor with a wide tissue distribution (24, 30). Although the full range of its biological roles remains uncertain, its functions in the regulation of systemic Ca metabolism are well established in parathyroid (5) and kidney (31). Isolated hypoparathyroidism is a disorder of Ca homeostasis that results from a variety of causes, which include gain-of-function mutations in the CaR.
Analysis of the CaR gene in the present study in 19 unrelated patients
presenting with isolated, symptomatic hypoparathyroidism revealed 5
previously described (Fig. 1 and references 7–23) and 3 new mutations.
Assessment of the biological functions of these mutations in
vitro confirmed gain-of-function in seven. The other mutation,
Ala843Glu, led to constitutive activation of the CaR, as previously
described (17).
The CaR is characterized by a very large (
600 amino acids)
amino-terminal extracellular domain, seven TM domains, and a long
carboxyl-terminal intracellular tail (6). Four missense
mutations were found within the first third of the extracellular
domain, and the three others were located within two of the last three
TMs (TM 5 and TM 7) and in the third intracellular loop. This confirms
the presence of two "hot spots" for activating missense mutations
within the CaR gene that encode exons 3–4 and 7. The first hot spot
involves the extracellular domain, an essential portion of the receptor
involved in N-linked glycosylation, cell surface expression,
dimerization, and ligand binding (32, 33, 34, 35, 36, 37, 38). Eight of the 26
activating mutations so far described are located within this
extracellular domain between Ala116 and Pro136, which is thought to be
a key region for the maintenance of an inactive conformation of CaR
(39). The second hot spot for activating mutations
involves domains participating in the activation of the associated G
proteins of the CaR, although it is still not known at a molecular
level how ligand binding by the CaR is transduced into G protein
activation (40).
The high incidence of CaR gene mutations (42%) in our 19 index patients with isolated hypoparathyroidism makes the screening of the CaR gene an important step in the work-up of this endocrine disorder, especially in hypocalcemic patients with inappropriately normal urinary Ca excretion at presentation (e.g. relative hypercalciuria) (22). This mutational analysis is also an essential medical tool for the evaluation of children presenting with isolated hypoparathyroidism without a clear mode of inheritance. Indeed, the finding of a de novo mutation in the CaR gene can exclude others causes, such as autoimmune poly-endocrinopathy-candidasis-ectodermal dystrophy, that would otherwise require complex, long-term medical surveillance for the detection of other endocrine abnormalities (41).
Molecular and biochemical screening of 54 members of the eight families studied here with point mutations or a deletion within the CaR gene showed complete segregation of hypocalcemia with the alteration in the CaR gene. There is excellent concordance between genotype (presence or absence of CaR mutation) and simple biochemical phenotype (presence or absence of hypocalcemia). Thus, the measurement of serum Ca concentration may be used as a sensitive, inexpensive, and rapid test for family screening once an activating mutation of the CaR gene has been identified in an index patient with isolated hypoparathyroidism.
In the present study, we also had the opportunity to analyze clinical and biochemical data obtained at the time of diagnosis of hypocalcemia in a total of 21 patients with an activating mutation of the CaR gene. Moreover, we have summarized biochemical and clinical data accumulated during treatment of 14 of these 21 patients for periods of time ranging from 1–17 yr. Because the CaR gene was cloned in 1993, most of these data are retrospective.
Our studies show wide variability in the clinical presentation of hypocalcemia, ranging from severe seizures to the total absence of symptoms, even after careful questioning. It is noteworthy that only 4 of the 21 affected patients had severe clinical signs of hypocalcemia early in life. Most patients with an activating mutation of the CaR had either asymptomatic hypocalcemia (n = 7) or no apparent clinical manifestations until adulthood, when they were first diagnosed at 23–52 yr of age (n = 6). This suggests that activating CaR mutations may be more common than currently recognized in the general population. The severity of the clinical presentation is inversely related to the level of serum Ca concentration, but the severity of hypocalcemia and the resulting clinical features do not depend on the type of CaR gene mutation that is present. In addition, patients within the same family exhibited differing clinical presentations, and serum Ca levels were not related to the gain-of-function of the mutant receptors as assessed in vitro. Three children with de novo mutations presented with severe neonatal hypocalcemia. It might be argued that gestation in a normal mother suppressed the parathyroids of these affected fetuses, thereby accentuating the mild hypocalcemia that normally occurs in the immediate postnatal period and producing severe neonatal hypocalcemia. This would be analogous to the gestation of a normal fetus in a hyperparathyroid mother, which can be associated with severe neonatal hypocalcemia (42). If this were the case, patients 4-II1, 4-II2, 6-III3, 8-III5, and 8-III6, who were born to an affected father but an unaffected mother, would also have been expected to exhibit severe neonatal hypocalcemia, but this was not the case. It is most likely, therefore that additional factors modify the hypocalcemic action of the activating mutations of the CaR gene in some affected infants, such as vitamin D deficiency at birth, vitamin D or Ca deficiency of the mother during pregnancy, or other processes such as infections or severe injury (43, 44, 45).
Once the diagnosis of an activating CaR mutation has been made, the need for therapeutic correction of the hypocalcemia remains an open question. Six patients had severe hypocalcemic manifestations requiring emergency treatment with Ca infusion and oral administration of a 1-hydroxylated form of vitamin D3, but the 15 other patients had either no symptoms or mild signs and symptoms of hypocalcemia. Moreover, overly zealous correction of hypocalcemia may be deleterious to renal function in these patients, because their low circulating levels of PTH and their pathological activation of the CaR in the renal tubule (46, 47, 48) decrease the tubular reabsorption of Ca, and increase the risk for hypercalciuria, which is the most common metabolic abnormality associated with nephrocalcinosis (49). Our analysis of the 14 patients compliant with treatment emphasizes this risk, because 9 of them experienced hypercalciuric episodes during treatment.
Eight of these nine patients had nephrocalcinosis detected by renal
ultrasound after having been treated for more than 1 yr. Thus the
incidence of nephrocalcinosis [57% (9 of 14)] appears to be
especially high in treated patients harboring a gain-of-function
mutation of the CaR. Even though none of these patients had biochemical
evidence of impaired renal function, and nephrocalcinosis disappeared
in one case after reduction of the dosage of the 1 D3, the
prevalence of nephrocalcinosis in these patients emphasizes the need
for prolonged, careful medical follow-up during treatment with
1-hydroxylated forms of vitamin D. The present analysis of the
biochemical data collected in these 14 treated patients clearly shows
that the level of serum Ca is not a very good predictor of
hypercalciuria and nephrocalcinosis, because both conditions can
develop while serum Ca remains below the normal range. Moreover, no
clear cut-off point was evident for the serum Ca level at which
nephrocalcinosis developed. Therefore, close monitoring of urinary Ca
excretion and its maintenance below the upper limit of the normal range
is crucial to avoid the occurrence of nephrocalcinosis.
Based on the present retrospective analysis of data recorded during a total of 103 treatment years in 14 patients, we propose the following guidelines for treatment. Because the aim of vitamin D administration is to correct or prevent the occurrence of clinical symptoms of hypocalcemia, all severely symptomatic patients should be treated. In contrast, the decision to initiate treatment should be carefully evaluated on a case-by-case basis in asymptomatic or mildly symptomatic patients. One might consider recommending treatment to patients with serum Ca levels below 1.95 mmol/liter, regardless of their age at diagnosis, because none of the patients with severe signs of hypocalcemia had serum Ca values above this threshold. Once treatment is initiated, the dose of 1-hydroxylated vitamin D3 should be kept as low as possible, and the patients should be closely monitored to avoid prolonged episodes of hypercalciuria, irrespective of the level of serum Ca. Achieving this goal requires regular follow-up of urinary Ca excretion on 24-h urine samples or spot urine samples during infancy, every 3–6 months. In cases with persistently severe, symptomatic hypocalcemia, despite vitamin D dosages leading to clear hypercalciuria, thiazide diuretics (14) or, in the future, synthetic PTH (23) or CaR antagonists (50) may offer a complementary strategy to limit the risk of nephrocalcinosis.
In conclusion, molecular exploration of the CaR gene should be considered during the initial work-up of idiopathic isolated hypoparathyroidism and has potentially important clinical relevance for the patient’s clinical outcome. Prospective studies of large homogenous populations are required to more precisely define the alterations in Ca homeostasis that are associated with CaR gene abnormalities, their clinical consequences, and their optimal therapeutic management.
Acknowledgments
We thank Prof. A. Raisonnier for the opportunity to work in his department (Service de Biochimie A, Pitié Salpétrière, Paris, France), as well as Drs. F. Archambeaud-Mouveroux (Service d’Endocrinologie Adulte, Centre Hospitalier Universitaire, Limoges, France), F. Bonnet-Boutillon (Médecin Généraliste, Sancheville, France), L. David (Département de Pédiatrie, Centre Hospitalier Universitaire, Edouard Herriot, Lyon, France), F. Huet (Département de Pédiatrie, Centre Hospitalier Universitaire, Dijon, France), O. Puel (Département de Pédiatrie, Center Hospitalier Universitaire, Bordeaux, France), C. Sinding (Centre de la Recherche Scientifique, Unité Propre de Recherche 1524, Hôpital saint Vincent de Paul, Paris, France), R. Trèves (Service de Rhumatologie, Centre Hospitalier Universitaire, Limoges, France), and G. Turpin (Service d’Endocrinologie, Centre Hospitalier Universitaire, Pitié Salpétriere, Paris, France) for clinical support.
We also are grateful to L. Zekraoui (Service de Biochimie A, Centre Hospitalier Universitaire Pitié Salpétriére, Paris, France) and to Suchih Sun (Brigham and Women’s Hospital, Boston, MA).
Footnotes
This work was supported by The Faculté de Médecine de Limoges, L’Assistance Publique-Hôpitaux de Paris, France; by The St. Giles Foundation (to E.M.B.); and by NIH Grants DK52005 (to E.M.B.), DK48330 (to E.M.B.), and DK54934 (to M.B.).
Abbreviations: 1 (OH)D3, 1-Hydroxylated
analogues of vitamin D3; C-, carboxyl-terminal; CaR, Ca-sensing
receptor; TM, transmembrane; WT, wild-type.
Received September 18, 2000.
Accepted July 26, 2001.
References
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, previously described mutations; #,
mutations described in the present study; coding exons are indicated in
brackets (
