(Circulation. 1996;93:1702-1708.)
© 1996 American Heart Association, Inc.
Articles |
Latent Hypoparathyroidism in Children With Conotruncal Cardiac Defects
From the Section of Cardiology, Department of Pediatrics (B.F.C., A.C.) and the Division of Pediatric Cardiothoracic Surgery, Department of Surgery (M.N.I., V.R.), Rush University Medical School, Chicago; the Division of Nephrology and Mineral Metabolism, Department of Pediatrics (C.B.L.), Northwestern University Medical School, Chicago; the Division of Epidemiology and Biostatistics, School of Public Health (M.N.I., V.R.), University of Illinois at Chicago; and the Division of Human Genetics and Molecular Biology (D.A.D.), Children's Hospital of Philadelphia.
Correspondence to Bettina F. Cuneo, MD, Section of Pediatric Cardiology, Rush Children's Hospital, 1653 W Congress Pkwy, Chicago, IL 60612.
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Abstract |
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Background DiGeorge anomaly is characterized by hypoplasia or atresia of the thymus and parathyroid glands resulting in T cell–mediated immune deficiency, hypocalcemic hypoparathyroidism, and conotruncal cardiac defects. It usually is associated with deletions of chromosomal region 22q11. We hypothesized that the stimulated (secretory reserve) but not the constitutive secretion of parathyroid hormone would be reduced in normocalcemic children with conotruncal cardiac defects but no overt immune deficiency and would be related to the presence of a deletion in the DiGeorge chromosomal region of 22q11.
Methods and Results Blood-ionized calcium and serum-intact parathyroid hormone were measured at baseline and seven more times during hypocalcemia induced during cardiopulmonary bypass in 22 patients and 10 control subjects with an atrial septal defect. Chromosomal deletions were detected by fluorescent in situ hybridization and DNA dosage analysis. There were no differences in basal calcium and parathyroid hormone levels between patients and control subjects. All had increased parathyroid hormone in response to hypocalcemia; despite lower calcium levels, parathyroid hormone levels were lower in patients. The parathyroid hormone secretory reserve in 14 of 22 patients was reduced compared with control subjects; 4 of the 14 had deletions.
Conclusions A significant number of children with conotruncal cardiac defects have normocalcemia and a normal constitutive level of parathyroid hormone but deficient parathyroid hormone secretory reserve; about 30% also have 22q11 deletions. Such children may be at risk for the later development of hypocalcemic hypoparathyroidism.
Key Words: genetics • heart defects, congenital • tetralogy of Fallot • calcium • truncus arteriosus
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Introduction |
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DGA is a developmental field defect of the third and fourth pharyngeal pouches characterized by a spectrum of thymic and parathyroid gland abnormalities and CTCD,1 2 3 including type B interrupted aortic arch, persistent truncus arteriosus, and tetralogy of Fallot. Thymic and parathyroid gland aplasia with CTCD are seen in the most severely affected individuals with DGA and produce T cell–mediated immune deficiencies and hypoparathyroidism, respectively.1 2 3 Milder or partial forms of DGA also have been described in which more subtle abnormalities of T cell–mediated immunity are present.3 4 5 6 7 Still other patients with CTCD and a family history of DGA remain normocalcemic with measurable parathyroid hormone but demonstrate a deficient response to EDTA-induced hypocalcemia. This has been called latent hypoparathyroidism.8
To date, no specific gene defect has been identified as the cause of DGA, although a candidate region on chromosome 22q11 has been shown to be deleted in the majority of patients.9 10 11 There does not appear to be a correlation between the presence of specific clinical findings and the size of the deletions; patients with overt T-cell abnormalities and hypocalcemia from hypoparathyroidism show the same deletions as patients with more subtle immunologic and biochemical manifestations.10 12 13 14
Because the same deletion seen in DGA has been demonstrated in 15% of children with apparent isolated CTCD,15 we hypothesized that such patients might have additional subtle characteristics of DGA. In this report, we describe the response of iPTH secretion to evoked hypocalcemia in children with CTCD. Our data demonstrate that >50% of these children have a reduced secretory response of iPTH compared with control subjects. These findings suggest that patients with CTCD should have prolonged follow-up of their calcium homeostasis.
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Methods |
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Patient Selection
Patients and control subjects were selected from consecutive children and young adults (age, 3 months to 28 years) with either CTCD (patients)—including persistent truncus arteriosus (n=4), interrupted aortic arch type B (n=2), and tetralogy of Fallot with pulmonary stenosis or pulmonary atresia (n=16)—or secundum ASD (control subjects) undergoing CPB between March 1993 and February 1994 at Christ Hospital and Rush Children's Hospital, Chicago, Ill (Table 1
). The investigative
protocol was approved by the Human Investigation Committee at both
institutions, and parental consent was obtained for all subjects.
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Twenty-two patients (12 boys, 10 girls; median age, 6 months; mean
age, 7.5 months; range, 1 month to 18 years) with CTCD and 10 control
subjects (4 boys, 6 girls; median age, 32 months; mean age, 35 months;
range, 11 months to 28 years) with secundum ASD participated in the
study (Table 1
). Indications for surgery among the patients included
intracardiac repair at 2 to 13 months of age in 12 patients with
acyanotic tetralogy of Fallot and 2 palliated with a systemic to
pulmonary artery shunt; right ventricle to pulmonary
artery homograft or pulmonary valve replacement in 3 with
tetralogy and 2 with persistent truncus arteriosus;
ventricular septal defect closure with resection of
subaortic stenosis in 2 with type B interrupted aortic arch;
and primary repair in a neonate with persistent truncus arteriosus and
interrupted aortic arch. All but the last patient were electively
admitted, all had oxygen saturations >88%, and all but 2 weighed
between the 10th and 95th percentiles for age.
Patients with secundum ASD were chosen as the control group because isolated ASD has rarely been reported in DGA or VCF, a phenotypically similar defect that also is associated with 22q11 deletions.13 15
Because patients with CTCD are a heterogeneous group with respect to pathogenesis and associated clinical features, a detailed history was obtained on each patient that included the occurrence of learning disabilities and speech impairment (when appropriate for the patient's age); frequent infections or reactions to blood transfusions; seizures, hypocalcemia, or parathyroid disease; maternal diabetes; or prenatal exposure to teratogens associated with CTCD. Each participant was evaluated by a single observer for dysmorphic features common to DGA or VCF.3 15
None of the control subjects had a family history of congenital heart disease, whereas 2 of the 22 CTCD patients did: patient 1 had a first cousin with Ebstein malformation of the tricuspid valve, and the father of patient 4 had a ventricular septal defect. The father of patient 21 developed seizures and immune deficiency in his 30s. The mother of patient 22 was a "slow learner." None of the patients were developmentally delayed or had a history of learning disabilities, frequent infections, reactions to blood transfusion, seizures, hypocalcemia, or parathyroid disease. Prenatal histories were unremarkable except for maternal insulin-dependent diabetes in patient 7 and maternal recreational drug abuse (heroin and crack cocaine) in patient 15.
Seven patients had dysmorphic features. Patient 2 had low-set, posteriorly rotated ears and a small mouth with a short philtrum. Patient 22 had a prominent nasal tip and small, almond-shaped eyes. Patients 12 and 18 had broad nasal tips and slender digits. In addition, 2 of the 7 had extracardiac anomalies: anal atresia (patient 18) and club feet (patient 22). None had features specific to VCF, although hypernasal speech could not be evaluated in the youngest infants.
Molecular-Cytogenetic Studies
Fluorescent In Situ Hybridization
Peripheral blood lymphocyte cultures were
established on each patient. Metaphase chromosome spreads were prepared
from the lymphocytes by standard techniques and hybridized with a
cosmid DNA probe for N25 (D22575), a proximal marker in the DGCR of
22q11.16 Cosmid probe cos82, previously localized to the
distal long arm of chromosome 22, was used as a control probe to
identify chromosome 22.17 Hybridization was detected with
avidin conjugated to fluorescein (Enzo Biochem). Copy
number was assessed by use of a modified Zeiss universal inverted
microscope.
DNA Dosage Studies
Genomic DNA was extracted from blood lymphocytes by standard
methods18 and digested with restriction enzyme
HindIII according to the manufacturer. Digested DNA was
separated by gel electrophoresis and transferred to Hybond
N+ by use of the method of Southern.19 Probe
N41(D225788), isolated from a Not I linking library and localized to
the distal DGCR by somatic cell hybrid mapping, was used to assess the
extent of the deletion and exclude the possibility of smaller deletions
distal to N25.20
Quantitative hybridization of genomic DNA from patients and control subjects was performed in triplicate to determine copy number at the test locus. Filters were hybridized simultaneously with the test probe N41 and control probe H2-27, which maps to chromosome 11, which is not implicated in DGA.20 Copy number at the test locus was assessed by previously described methods.9
Peripheral Blood Studies
Lymphocytes
Total numbers of and percent lymphocyte cells were measured by
standard techniques.21 The absolute and percent T and B
cells and selected T-cell subset ratios—helper-inducer
(T4-CD4), suppressor-cytotoxic (T8-CD8), helper-suppressor
(CD4-CD8), and natural killer cells (NKH-1–CD56)—were determined by
flow analysis with standard monoclonal antibody
techniques.22
Blood-Ionized Ca2+ and iPTH Measurements
The hypocalcemic challenge of CPB served as the
provocative test of iPTH reserve. Ca2+ levels
commonly fall to 50% below baseline on infusion of priming solutions
with citrated blood products and electrolyte solutions without
calcium. These effects are increased further with alkalosis and
hypothermia.23 24 25 26
After induction of general anesthesia, blood was obtained for serum Ca2+ and iPTH measurements (sample 1). Once CPB was initiated, Ca2+ and iPTH were sampled according to the following schedule: 5 minutes after the establishment of CPB (sample 2), at the beginning of cooling (sample 3), 15 minutes after the initiation of cooling (sample 4), at the lowest temperature (sample 5), at the onset of rewarming (sample 6), immediately before separation from CPB (sample 7), and 15 minutes after intravenous calcium was infused to correct hypocalcemia (sample 8).
Ca2+ concentration and pH were measured immediately from venous or arterial samples with a GemStat (Mallinkrodt) analyzer. The normal range for Ca2+ on this instrument is 0.99 to 1.2 mmol/L. Sera were stored at -20°C until the iPTH measurement. iPTH was measured in triplicate with a modification of an immunoradiometric assay (Incstar intact PTH SP).27 The range in children with normal Ca2+ is 15 to 55 pg/mL. The assay reliably detects physiological elevations in iPTH during hypocalcemia and reductions below 15 pg/mL during hypercalcemia in patients without DGA. Intra-assay and interassay variabilities were 5% and 8%, respectively, for iPTH values between 3 and 300 pg/mL.
Statistical Analysis
Values are reported as mean±SD. Differences in mean values for
T cells, B cells, and T-cell subsets between the control subjects and
patients were compared by the Mann-Whitney nonparametric
test and linear regression technique with age as a covariate. Mean
Ca2+ and iPTH levels for samples 1 through 8 were compared
between groups by Student's two-tailed t test. The
Ca2+-iPTH relationship was evaluated by linear regression
analysis after log transformation because iPTH is not normally
distributed. The slope of the mean regression line in the control
population was compared with the individual slopes of the patients by a
t test. Regression data are presented as
mean±SEE.
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Results |
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Molecular-Cytogenetic Studies
No control subjects showed deletions by fluorescent in situ hybridization for the N25 probe or by dosage analysis with the N41 probe. In contrast, 4 of 22 CTCD patients (18%) had 22q11 deletions by fluorescent in situ hybridization and dosage analysis: Both N25 and N41 were deleted in patients 2 (interrupted aortic arch) and 12 (tetralogy of Fallot with pulmonary atresia); only N25 was deleted in patients 18 (truncus arteriosus) and 22 (tetralogy of Fallot).
Lymphocyte Studies
There was an increase in total T cells, CD4 cells, and the ratio
of CD4 to CD8 cells in CTCD patients compared with control subjects
(Table 2). However, the difference disappeared when age
was included as a covariate, consistent with previously
established findings of age-related differences in numbers of
lymphocytes within subsets.28
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Hypocalcemia and iPTH Response
Baseline Ca2+ (sample 1) was normal and iPTH was
measurable in all CTCD patients and control subjects. These values did
not differ between patients and control subjects: 1.19±0.07 mmol/L and
28±17 pg/mL versus 1.24±0.09 mmol/L and 35±14 pg/mL, respectively;
P=NS. The maximum decrement in Ca2+ for patients
and control subjects occurred 5 minutes after the establishment of CPB
(sample 2) and represented the lowest Ca2+
level measured during the study (Fig 1B). This maximum
decrement also resulted in a lower Ca2+ in patients
compared with control subjects at this time: 0.5±0.2 versus 0.8±0.2
mmol/L, P=.001. Thereafter, Ca2+ levels remained
below baseline values in each group and did not differ between patients
and the control subjects except in sample 6: 0.72±0.14 versus
0.83±0.13 mmol/L, respectively; P=.04. Infusion of
exogenous calcium raised the Ca2+ to baseline levels, and
the postinfusion Ca2+ did not differ between CTCD patients
and control subjects.
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) and CTCD (
) groups. Values shown are mean±SE. After
induction of general anesthesia, blood and serum were
obtained for Ca2+ and iPTH measurements (sample 1). Once
CPB was initiated, Ca2+ and iPTH were sampled according to
the following schedule: 5 minutes after CPB (sample 2), at the
beginning of cooling (sample 3), 15 minutes after the initiation of
cooling (sample 4), at the lowest temperature (sample 5), at the onset
of rewarming (sample 6), immediately before separation from CPB (sample
7), and 15 minutes after intravenous administration of
calcium (sample 8). Baseline Ca2+ and iPTH were normal in
both control and CTCD groups. Ca2+ in samples 2 through 7
were significantly less (P<.001) than in sample 1 for both
groups; Ca2+ in sample 8 was not different than in sample 1
for either group. Ca2+ was lower in samples 2 through 7 for
CTCD versus control subjects (P
.001). iPTH in samples 2
through 7 was significantly greater (P<.001) than in sample
1 for both groups; iPTH in sample 8 was not different than in sample 1
for either group. iPTH was significantly reduced in CTCD versus control
subjects in samples 2 through 7 (P
The reduction in Ca2+ was accompanied by a rise in iPTH in
each group (Fig 1A). The maximum increase occurred at the time of
sample 3 but was significantly less in CTCD patients than in control
subjects at that time: 121±52 versus 175±41 pg/mL, respectively;
P<.001. Thereafter, iPTH levels were greater than baseline
values within each group but always lower in patients compared with
control subjects. After exogenous calcium was infused, iPTH levels
declined to levels not different from baseline and to the same level in
both groups.
iPTH Reserve
We determined the relationship between Ca2+ and the
natural log of iPTH in control subjects (Fig 2). The
slope of the line that defined this relationship, called the iPTH
secretory reserve, was -1.51±0.4. We then evaluated the iPTH
reserve of the individual CTCD patients. CTCD patients fell into one of
two subgroups: 8 patients whose iPTH secretory reserves were no
different than those of control subjects (mean slope=1.64±0.25,
P=NS; Fig 3A), and 14 patients whose iPTH
secretory reserves were significantly less than those of control
subjects (mean slope=-0.22±0.28, P<.0001; Fig 3B).
There was no difference in the iPTH secretory reserve of the two CTCD
groups based on the length of time on CPB (data not shown). There was
no association between the iPTH secretory reserve with patient age,
sex, or type of CTCD as a covariate.
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Of the 14 patients with a reduced iPTH secretory reserve, 4 (29%) were deleted in the DGCR: patients 2, 12, 18, and 22. These 4 patients had dysmorphic features. However, 3 additional patients (patients 10, 19, and 20) who were dysmorphic but without deletions in the DGCR had normal iPTH secretory reserves. Finally, 7 patients with reduced iPTH secretory reserves were neither dysmorphic nor deleted in the DGCR.
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Discussion |
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Even mild hypocalcemia evokes a rapid and sustained increase in iPTH levels in infants, children, and adults.28 Results from this study demonstrated that in children with CTCD who are normocalcemic at rest, 50% have a reduced ability to secrete iPTH in response to evoked hypocalcemia compared with a control population of children with ASD. We have called this response latent hypoparathyroidism, and it implies a reduced iPTH secretory reserve.
We demonstrated latent hypoparathyroidism previously in an adult with CTCD whose child had DGA. She had normal resting Ca2+ but lacked the ability to increase mm-iPTH in response to hypocalcemic stress.8 Additionally, the asymptomatic father of a son with DGA had a diminished mm-iPTH response to hypocalcemia from phosphate loading.29 We can now extend this phenomenon of latent hypoparathyroidism to include a substantial portion of children with CTCD and normal T-cell subsets without a family history of DGA or VCF.
It is apparent that patients with CTCD represent a heterogeneous group with respect to pathogenesis and phenotype. CTCD with hypoplasia of the thymus and parathyroid gland, learning disabilities, and dysmorphic facies have been described in DGA, VCF, and conotruncal anomalies face syndrome.13 30 31 Common to these disorders, and in a small percentage of patients with only CTCD, are deletions in the DGCR of chromosome 22q11.9 10 17 32 33 Our patients with CTCD had no overt findings of the 22q11 deletion syndromes such as immune deficiencies, cleft palate, or hypoparathyroidism. However, 4 patients with latent hypoparathyroidism and 22q11 deletion had dysmorphic features. Perhaps other subtle manifestations suggestive of the 22q11 deletion syndromes such as learning disabilities, antisocial personality, or speech abnormalities may develop in these patients over time.
Two patients in our report were without deletions in the DGCR or facial dysmorphism but had a family history of cardiac defects unassociated with a 22q11 deletion syndrome. The origin of the CTCD in these patients may be different from that of an infant of a diabetic mother or a child born after exposure to teratogens because CTCD with DGA in deletion-negative patients has been linked causally with such exposures.34
At this time, neither the genes nor the environmental factors responsible for CTCD are known. It is possible that the 10 deletion-negative patients with reduced iPTH secretory reserve in this report have smaller chromosomal deletions that could not be detected by the probes used here or have a point mutation in a critical gene within the DGCR. We are pursuing such possibilities to explain the differences in iPTH responsiveness in our patients.
Potential causes of functional iPTH deficiency during hypocalcemia have been evaluated in our patients. Hypomagnesemia may limit the secretory response of the parathyroid gland to hypocalcemia,35 but none of the patients were hypomagnesemic (data not shown). There was an age difference between the control subjects and patients, which might have influenced the iPTH secretory reserve independent of cardiac lesion. Patients with secundum ASD were chosen as a control group because this homogeneous group most closely approximates a normal population and is the least frequently associated cardiac defect in the 22q11 deletion syndrome and because we were unaware of data supporting age-related differences in iPTH responsiveness. In fact, previous studies have shown the iPTH response during hypocalcemia to be independent of age. Regardless of gestational age, neonates between 1 and 2 weeks of age had more-than-double PTH secretion within 5 minutes of undergoing partial exchange transfusion for hyperbilirubinemia.36 Further, in adults with hypocalcemia during CPB,37 the extent of PTH response was not different than in the neonates or the patients and control subjects in the current study. Using a similar protocol reported in the current study, Robertie et al23 found the iPTH response in 12 infants <2 years of age who were undergoing CPB to be no different than those of children 24 to 78 months of age or adults. Additionally, a lower Ca2+ level should evoke at least an equivalent iPTH response; not only was hypocalcemia more profound in CTCD patients compared with control subjects, but there was no difference in the degree or duration of hypocalcemia in CTCD compared with the reduced iPTH secretory reserve. Therefore, we can conclude that the age of patients with CTCD did not influence our findings.
The length of time of the hypocalcemic stimulus may influence the mechanism of the rise in iPTH: hormone secretion in dispersed and cultured porcine and bovine parathyroid cells is increased without an attendant increase in gene transcription rates when hypocalcemia is present for minutes to hours.37 38 In contrast, with conditions of prolonged hypocalcemia in isolated bovine parathyroid cells39 and the rat in vivo,40 41 rates of gene transcription increase, and the percentage of hormone-secreting cells in the parathyroid gland may increase.42 Because the hypocalcemic stimulus was present for minutes to hours in both CTCD patients and control subjects, we conclude that there was no difference in the mechanism of increased iPTH secretion.
The natural history of latent hypoparathyroidism remains unknown. Hypocalcemic hypoparathyroidism had developed after normocalcemia in 2 patients with CTCD and a family history of DGA.43 Additionally, hypocalcemia has been known to recur during adolescence in patients with VCF.44 Thus, we raise the possibility that patients with CTCD and a reduced iPTH reserve may develop symptomatic hypocalcemia from hypoparathyroidism later in life.
The cause of latent hypoparathyroidism in CTCD is unknown. Because of the phenotypic similarities after neural crest cell ablation in the chick embryo model with abnormalities seen in the 22q11 deletion syndromes, we speculate that such a deletion may induce aberrations of cephalic neural crest formation or migration. This might result in an as-yet-uncharacterized defect that becomes manifest only during provoked hypocalcemia and arises from functional parathyroid gland hypoplasia or in an anatomically normal mass of tissue. The finding of functional abnormalities of the parathyroid gland in CTCD patients supports the hypothesis that a common developmental abnormality of neural crest cells results in abnormalities of diverse organ systems.
We conclude that children with CTCD need careful evaluation for additional, more subtle findings of the 22q11 deletion syndromes such as latent hypoparathyroidism. In addition, many may have latent hypoparathyroidism in the absence of detectable deletions in the DGCR. Physiological stresses that compromise normal resting Ca2+ levels may place such patients at risk for the acute and chronic sequelae of hypocalemia. Whether latent hypoparathyroidism will precede and predict hypocalcemic hypoparathyroidism requires further investigation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a Rush University Institutional Grant. We acknowledge the invaluable participation of the following individuals: for patient recruitment: Katie Tubeszewski, RN, Natalie Gates-Rudolph, RN, Beth Hemker, PA-C, and Craig Adams, MD; for sample collection: perfusionists Jim Tardy, Vince Rizzo, and Mike Djurick; for patient referral: attending cardiologists at the Heart Institute for Children and the Children's Heart Center; for technical assistance: Dawn E. Sailer, MS, Carol Klinsky-Grant, BS, Josh Salvin, MS, and Mengrong Li, MD; and for manuscript preparation: Debbie Muse. Special thanks go to Marcia L. Budarf, PhD, for providing probe N41 (D225788) and Joe Hoo, MD, for his encouragement during the early phases of the study.
Received September 5, 1995; revision received November 7, 1995; accepted November 13, 1995.
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