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Transient congenital hypoparathyroidism: How transient is it?
866
Clinical and laboratory observations
16. Genton E, Barnett HJM, Fields WS, Gent M, Hoak JC. Cerebral ischemia: the role of thrombosis and of antithrombotic therapy: study group on antithrombotic therapy. Stroke 1977;8:150-75.
The Journal of Pediatrics December 1987
17. Ratnam S, March S, Ojah C, et al. Hemolytic-uremic syndrome associated with verotoxin-producing Escherichia coll. Can Med Assoc J 1985;133:37-8.
Transient congenital hypoparathyroidism: How transient is it? R, Bainbridge, MBBS,Z. Mughal, MRCP,F. Mimouni, MD, and R. C, Tsang, MBBS From the Division of Neonatology, Department of Pediatrics, University of Cincinnati Medical Center, the Perinatal Research Institute, and Children's Hospital Research Foundation, Cincinnati
The pathogenesis of transient congenital (idiopathic) hypoparathyroidism is unknown, but it is believed t h a t patients will fully recover. TM T h e criteria for diagnosis are (1) hypocalcemia and h y p e r p h o s p h a t e m i a requiring treatm e n t with pharmacologic doses of vitamin D and calcium gluconate, (2) low serum P T H concentrations, and (3) complete recovery within a few months. W e hypothesized t h a t recovery from T C H P m a y represent a " c o m p e n s a t e d " form of hypoparathyroidism r a t h e r t h a n a true "resolution" of the disorder. To test our hypothesis, we subjected (after obtaining informed parental consent) a patient who fulfilled the diagnostic criteria for T C H P to an E D T A infusion to assess her P T H response to hypocalcemia.
mg/dL (2.36 mmot/L), chest radiograph (normal with a normal eardiothymic silhouette), urine toxicology, and aminoaciduria screen (negative). Blood T-lymphocyte number and response to phytohemagglutinin stimulation were normal. Head ultrasonographic examination and electroencephalogram were normal. The infant's serum calcium concentration was corrected by intravenous calcium gluconate, but attempts to "wean" her from intravenous calcium led to a relapse of hypocalcemia. At this time hypoparathyroidism was suspected, and the patient and her parents were studied for possible parathyroid disorders. The total serum calcium, phosphorus, and parathyroid hormone concentrations of both parents were within the normal range. A magnesium infusion study 5 was performed on the patient on the twelfth day of life to exclude the possibility of a transient hypoparathyroidism
CASE REPORT The patient was a white female infant, born to a 32-year-old mother. The pregnancy was complicated by chronic hypertension and a short episode of preeclampsia. Gestational diabetes was excluded by a normal glucose challenge test at 28 weeks gestation. The infant was delivered by repeat cesarean section at term and was slightly small and short for gestational age (birth weight 2180 g and length 47 cm). Apgar scores were 8 and 10 at 1 and 5 minutes, respectively. Physical examination was unremarkable. On the third day of life, focal and generalized tonic clonic movements were noted, and the infant was transferred to Children's Hospital Medical Center. Investigations included complete evaluation for sepsis (normal), blood electrolytes (normal), serum total calcium concentration (5.3 mg/dL) (1.32 mmol/L), serum magnesium (1.3 mg/dL) (0.54 mmol/L)), serum phosphate (7.3
Supported in part by National Institutes of Health Grant HD 11725, U.S. PuNic Health Service training in perinatal care, and Research Grant MCH MCT 000174, and National Institutes of Health Perinatal Emphasis Research Center Grant HD 20748. Submitted for publication May 18, 1987; accepted July i0, 1987. Reprint requests: R. Bainbridge, M.B.B.S., University of Cincinnati College of Medicine, 231 Bethesda Ave., Cincinnati, OH 45267-0541.
PTH TCHP iPTH EDTA 25(OH)D
Parathyroid hormone Transient congenital (idiopathic) hypoparathyroidism Parathyroid hormone (immunoreactive) Ethylenediaminetetraacetic acid 25-Hydroxyvitamin D
caused by magnesium deficiency. In spite of a significant increase in the serum magnesium concentration (from 1.2 to 2.2 mg/dL), the serum calcium levels did not increase (7.1 to 7.0 mg/dL), and serum iPTH, which was undetectable before the test, remained undetectable. Renal tubular reabsorption of phosphorus was 90% (normal >85%), 6 consistent with hypoparathyroidism. The infant was given oral calcium gluconate and 25(OH)D, requiring up to 8 #g 25(OH)D/kg/day and 90 mg elemental Ca/kg/day to maintain eucalcemia. She was discharged on the forty-sixth day of life receiving 6 #g 25(OH)D/kg/day and supplemental Ca gluconate providing 45 mg elemental Ca/ kg/day. The goal for therapy was a serum calcium concentration between 9 and 9.5 mg/dL (2.24 to 2.38 retool/L). From the time of discharge to the age of 15 months, serum
Volume 111 Number 6, part 1
Clinical and laboratory observations
867
Table. EDTA infusion study: serum Ca, ionized Ca, Mg, P, and PTH responses Time of responses in relation to E D T A infusion - 2 hr 0 hr + 30 min +1 hr + 2 hr To convert to mmol/L
Serum Ca concentration (mg/dL)
Serum iCa concentration (mg/dL)
9.0 9.0 7.8 8.8 8.7 X0.25
4.88 5.08 4.20 4.36 4.64 X0.25
calcium concentration varied between 9,5 and 10.5 mg/dL; serum iPTH concentrations became detectable bt/t remained in the low or low-normal range. The dose of 25(OH)D was progressively reduced and eventually discontinued at 15 months of age. At that time the infant was treated with a regular multivitamin supplement, providing 400 IU of vitamin D/day. The dose of calcium gluconate was also gradually reduced and discontinued approximately 2 months later. Her weight and height were persistently below the 5th percentile but were parallel to the normal growth curves, consistent with familial short stature. Physical examination was remarkable for significant enamel bypoplasia of the upper incisors. METHODS At 22 months of age an EDTA infusion study was performed. A detailed description of this test has been reported elsewhere. 7 Serum calcium and magnesium levels were measured by atomic absorption spectromctry. 8 The normal pediatric range for calcium in our laboratory is 8.6 to 10.9 mg/dL (2.15 to 2.72 retool/L) with an interassay coefficient of variation of 1.2%. The normal pediatric range for magnesium is 1.7 to 2.5 mg/dL (0.70 to 1.02 retool/L) with an interassay coefficient of variation of 2.8%. Serum ionized calcium is measured with the Radiometer ICA (Copenhagen, Denmark) according to methods adapted from Moore. 9 The normal pediatric range in our laboratory is 4.84 to 5.68 mg/dL (1.21 to 1.42 mmol/L) with an interassay coefficient of variation of 1.9%. Serum iPTH was measured by radioimmunoassay detecting the intact (1-84) molecule according t o a modification of the method of Arnaud with an antiserum raised in guinea pigs? ~ The antibody does not cross react with either the 35-84 or the 1-34 fragment. The serum standard is obtained from subjects with hyperparathyroidism. The normal pediatric range is 33 to 117 #L Eq/mL. The interassay coefficient of variation is < 15%. RESULTS In spite of an adequate fall in serum ionized calcium concentration, there was no increase in serum iPTH
Serum PTH concentration t~LEq/mL
35 25 <20 26 2__._22
Serum Mg concentration (mg/dL)
Serum P concentration (mg/dL)
1.9 1.9 1.6 1.7 1.8 x 0.41
4.7 4.6 3.9 4.3 4.6 x0.32
concentration (normal: increase of 24% from baseline in children) 7 (Table). DISCUSSION This infant's case depicts the typical history and presentation of a patient with TCHP. Transient hypoparathyroidism secondary to maternal hyperparathyroidism was ruled out in our patient by the finding of normal serum calcium, phosphorus, and iPTH concentrations in the mother. Functional hypoparathyroidism secondary to magnesium deficiency was ruled out by the magnesium infusion study. Prematurity, hypoglycemia, birth asphyxia, and phosphorus overload as a result of ingestion of cow's milk were not present. The mother had no gestational diabetes. The fact that the patient's serum calcium concentration is now normal and that she is fully compensated makes permanent isolated hypoparathyroidism a less likely diagnosis because, in this condition, withdrawal of therapy results in recurrence of hypocalcemia. A wide spectrum exists in the DiGeorge syndrome, in which hypoparathyroidism, thymic hypoplasia, immunologic deficiency, and Cardiovascular and head and neck anomalies may be variably combined.11 Whether our patient fits into one end of this spectrum is speculative. Against the diagnosis of DiGeorge syndrome are the normal cardiovascular system, thymus, and T-lymphocyte number and function. Other reports have emphasized the transient nature of hypocalcemia in TCHP 1,2,4; only a few have documented serum iPTH concentrations before and after the patient was fully recovered? There are no published reports on the PTH response to either magnesium infusion while the patient was still hypocalcemic or to hypocalcemia induced by EDTA infusion once the patient is fully recovered. Our patient did not have an increase in serum PTH concentration in response to a significant fall in serum ionized calcium concentration at a time when she was considered to be fully recovered from TCHP. We speculate that she has a "compensated" form of primary hypoparathyroidism in which the parathyroid glands can produce just enough PTH to allow for normal calcium homeostasis under basal
868
Clinical and laboratory observations
The Journal of Pediatrics December 1987
conditions but will not respond to a hypocalcemic stress. This parathyroid status theoretically may put our patient at risk for hypocalcemia during stress such as fever, which appears to precipitate hypocalcemia in patients with hypoparathyroidism/2 However, it is unclear whether there will be progressive and full recovery of the parathyroid glands or the "compensated" hypoparathyroid state is permanent. Only long-term evaluations can answer this question. REFERENCES
1. Fanconi A, Prader A. Transient congenital idiopathic hypoparathyroidism. Helv Paediatr Acta 1967;22:342-59. 2. Todt H, Eysold R, Korth G, Wunsche W. Transient hypoparathyroidism as a cause of spasms in the newborn. Padiatr Grenzgeb 1980;19:299-302. 3. Mallette L, Cooper J, Kirkland J. Transient congenital hypoparathyroidism: possible association with anomalies of the pulmonary valve. J PEDIATR 1982;101:928-3l. 4. Rosenbloom A. Transient congenital idiopathic hypoparathyroidism. South Med J 1973;66:666-70. 5. Mimouni F, Shaul P, Specker B, Tsang R. Magnesium (MG) infusion in preterm and term neonates: effects on calciotropic hormones and calcium (abstr). Pediatr Res 1986;20:415.
6. Drummond KN. In: Nelson WE, Behrman RE, Vaughn VC, eds. Nelson textbook of pediatrics, 12th ed. Philadelphia: WB Saunders, 1983:1307-14. 7. Tsang R, Chen I, McEnery P, et al. Parathyroid function tests with EDTA infusions in infancy and childhood. J PEDIATR 1976;88:250-6. 8. Sunderman FW Jr, Carroll JE. Measurements of serum calcium and magnesium by atomic absorption spectrometry. Am J Clin Pathol 1965;43:302-10. 9. Moore EW. Ionized calcium in normal serum, ultrafiltrates and whole blood, determined by ion-exchange electrodes. J Clin Invest 1970;49:318-34. 10. Dincsoy MY, Tsang RC, Laskarzewski P, et al. The role of postnatal age and magnesium on parathyroid hormone response during exchange blood transfusion in the newborn. J PEDIATR 1982;100:277-83. 11. Conley ME, Beckwith JB, Mancer JFK, Tenckhoff L. The spectrum of the DiGeorge syndrome. J PEDIATR1979;94:88390. 12. Halbert K, Tsang RC. Endocrine system. In: Gellis S, Kagan B, eds. Hypoparathyroidism: current pediatric therapy, 12th ed. Philadelphia: WB Saunders, 1983:306-8.
FELLOWSHIPS Available fellowships in pediatric subspecialties and those for general academic pediatric training are listed once a year, in May, in The Journal of Pediatrics. Each October, forms for listing such fellowships are sent to the Chairman of the Department of Pediatrics at most major hospitals in the United States and Canada. Should you desire to list fellowships, a separate application must be made each year for each position. All applications must be returned to The C. V. Mosby Company by February 15 of the listing year to ensure publication. Additional forms will be supplied on request from the Journal Editing Department, The C. V. Mosby Company, 11830 Westline Industrial Drive, St. Louis, M O 63146/314-872-8370.
Clinical and laboratory observations
16. Genton E, Barnett HJM, Fields WS, Gent M, Hoak JC. Cerebral ischemia: the role of thrombosis and of antithrombotic therapy: study group on antithrombotic therapy. Stroke 1977;8:150-75.
The Journal of Pediatrics December 1987
17. Ratnam S, March S, Ojah C, et al. Hemolytic-uremic syndrome associated with verotoxin-producing Escherichia coll. Can Med Assoc J 1985;133:37-8.
Transient congenital hypoparathyroidism: How transient is it? R, Bainbridge, MBBS,Z. Mughal, MRCP,F. Mimouni, MD, and R. C, Tsang, MBBS From the Division of Neonatology, Department of Pediatrics, University of Cincinnati Medical Center, the Perinatal Research Institute, and Children's Hospital Research Foundation, Cincinnati
The pathogenesis of transient congenital (idiopathic) hypoparathyroidism is unknown, but it is believed t h a t patients will fully recover. TM T h e criteria for diagnosis are (1) hypocalcemia and h y p e r p h o s p h a t e m i a requiring treatm e n t with pharmacologic doses of vitamin D and calcium gluconate, (2) low serum P T H concentrations, and (3) complete recovery within a few months. W e hypothesized t h a t recovery from T C H P m a y represent a " c o m p e n s a t e d " form of hypoparathyroidism r a t h e r t h a n a true "resolution" of the disorder. To test our hypothesis, we subjected (after obtaining informed parental consent) a patient who fulfilled the diagnostic criteria for T C H P to an E D T A infusion to assess her P T H response to hypocalcemia.
mg/dL (2.36 mmot/L), chest radiograph (normal with a normal eardiothymic silhouette), urine toxicology, and aminoaciduria screen (negative). Blood T-lymphocyte number and response to phytohemagglutinin stimulation were normal. Head ultrasonographic examination and electroencephalogram were normal. The infant's serum calcium concentration was corrected by intravenous calcium gluconate, but attempts to "wean" her from intravenous calcium led to a relapse of hypocalcemia. At this time hypoparathyroidism was suspected, and the patient and her parents were studied for possible parathyroid disorders. The total serum calcium, phosphorus, and parathyroid hormone concentrations of both parents were within the normal range. A magnesium infusion study 5 was performed on the patient on the twelfth day of life to exclude the possibility of a transient hypoparathyroidism
CASE REPORT The patient was a white female infant, born to a 32-year-old mother. The pregnancy was complicated by chronic hypertension and a short episode of preeclampsia. Gestational diabetes was excluded by a normal glucose challenge test at 28 weeks gestation. The infant was delivered by repeat cesarean section at term and was slightly small and short for gestational age (birth weight 2180 g and length 47 cm). Apgar scores were 8 and 10 at 1 and 5 minutes, respectively. Physical examination was unremarkable. On the third day of life, focal and generalized tonic clonic movements were noted, and the infant was transferred to Children's Hospital Medical Center. Investigations included complete evaluation for sepsis (normal), blood electrolytes (normal), serum total calcium concentration (5.3 mg/dL) (1.32 mmol/L), serum magnesium (1.3 mg/dL) (0.54 mmol/L)), serum phosphate (7.3
Supported in part by National Institutes of Health Grant HD 11725, U.S. PuNic Health Service training in perinatal care, and Research Grant MCH MCT 000174, and National Institutes of Health Perinatal Emphasis Research Center Grant HD 20748. Submitted for publication May 18, 1987; accepted July i0, 1987. Reprint requests: R. Bainbridge, M.B.B.S., University of Cincinnati College of Medicine, 231 Bethesda Ave., Cincinnati, OH 45267-0541.
PTH TCHP iPTH EDTA 25(OH)D
Parathyroid hormone Transient congenital (idiopathic) hypoparathyroidism Parathyroid hormone (immunoreactive) Ethylenediaminetetraacetic acid 25-Hydroxyvitamin D
caused by magnesium deficiency. In spite of a significant increase in the serum magnesium concentration (from 1.2 to 2.2 mg/dL), the serum calcium levels did not increase (7.1 to 7.0 mg/dL), and serum iPTH, which was undetectable before the test, remained undetectable. Renal tubular reabsorption of phosphorus was 90% (normal >85%), 6 consistent with hypoparathyroidism. The infant was given oral calcium gluconate and 25(OH)D, requiring up to 8 #g 25(OH)D/kg/day and 90 mg elemental Ca/kg/day to maintain eucalcemia. She was discharged on the forty-sixth day of life receiving 6 #g 25(OH)D/kg/day and supplemental Ca gluconate providing 45 mg elemental Ca/ kg/day. The goal for therapy was a serum calcium concentration between 9 and 9.5 mg/dL (2.24 to 2.38 retool/L). From the time of discharge to the age of 15 months, serum
Volume 111 Number 6, part 1
Clinical and laboratory observations
867
Table. EDTA infusion study: serum Ca, ionized Ca, Mg, P, and PTH responses Time of responses in relation to E D T A infusion - 2 hr 0 hr + 30 min +1 hr + 2 hr To convert to mmol/L
Serum Ca concentration (mg/dL)
Serum iCa concentration (mg/dL)
9.0 9.0 7.8 8.8 8.7 X0.25
4.88 5.08 4.20 4.36 4.64 X0.25
calcium concentration varied between 9,5 and 10.5 mg/dL; serum iPTH concentrations became detectable bt/t remained in the low or low-normal range. The dose of 25(OH)D was progressively reduced and eventually discontinued at 15 months of age. At that time the infant was treated with a regular multivitamin supplement, providing 400 IU of vitamin D/day. The dose of calcium gluconate was also gradually reduced and discontinued approximately 2 months later. Her weight and height were persistently below the 5th percentile but were parallel to the normal growth curves, consistent with familial short stature. Physical examination was remarkable for significant enamel bypoplasia of the upper incisors. METHODS At 22 months of age an EDTA infusion study was performed. A detailed description of this test has been reported elsewhere. 7 Serum calcium and magnesium levels were measured by atomic absorption spectromctry. 8 The normal pediatric range for calcium in our laboratory is 8.6 to 10.9 mg/dL (2.15 to 2.72 retool/L) with an interassay coefficient of variation of 1.2%. The normal pediatric range for magnesium is 1.7 to 2.5 mg/dL (0.70 to 1.02 retool/L) with an interassay coefficient of variation of 2.8%. Serum ionized calcium is measured with the Radiometer ICA (Copenhagen, Denmark) according to methods adapted from Moore. 9 The normal pediatric range in our laboratory is 4.84 to 5.68 mg/dL (1.21 to 1.42 mmol/L) with an interassay coefficient of variation of 1.9%. Serum iPTH was measured by radioimmunoassay detecting the intact (1-84) molecule according t o a modification of the method of Arnaud with an antiserum raised in guinea pigs? ~ The antibody does not cross react with either the 35-84 or the 1-34 fragment. The serum standard is obtained from subjects with hyperparathyroidism. The normal pediatric range is 33 to 117 #L Eq/mL. The interassay coefficient of variation is < 15%. RESULTS In spite of an adequate fall in serum ionized calcium concentration, there was no increase in serum iPTH
Serum PTH concentration t~LEq/mL
35 25 <20 26 2__._22
Serum Mg concentration (mg/dL)
Serum P concentration (mg/dL)
1.9 1.9 1.6 1.7 1.8 x 0.41
4.7 4.6 3.9 4.3 4.6 x0.32
concentration (normal: increase of 24% from baseline in children) 7 (Table). DISCUSSION This infant's case depicts the typical history and presentation of a patient with TCHP. Transient hypoparathyroidism secondary to maternal hyperparathyroidism was ruled out in our patient by the finding of normal serum calcium, phosphorus, and iPTH concentrations in the mother. Functional hypoparathyroidism secondary to magnesium deficiency was ruled out by the magnesium infusion study. Prematurity, hypoglycemia, birth asphyxia, and phosphorus overload as a result of ingestion of cow's milk were not present. The mother had no gestational diabetes. The fact that the patient's serum calcium concentration is now normal and that she is fully compensated makes permanent isolated hypoparathyroidism a less likely diagnosis because, in this condition, withdrawal of therapy results in recurrence of hypocalcemia. A wide spectrum exists in the DiGeorge syndrome, in which hypoparathyroidism, thymic hypoplasia, immunologic deficiency, and Cardiovascular and head and neck anomalies may be variably combined.11 Whether our patient fits into one end of this spectrum is speculative. Against the diagnosis of DiGeorge syndrome are the normal cardiovascular system, thymus, and T-lymphocyte number and function. Other reports have emphasized the transient nature of hypocalcemia in TCHP 1,2,4; only a few have documented serum iPTH concentrations before and after the patient was fully recovered? There are no published reports on the PTH response to either magnesium infusion while the patient was still hypocalcemic or to hypocalcemia induced by EDTA infusion once the patient is fully recovered. Our patient did not have an increase in serum PTH concentration in response to a significant fall in serum ionized calcium concentration at a time when she was considered to be fully recovered from TCHP. We speculate that she has a "compensated" form of primary hypoparathyroidism in which the parathyroid glands can produce just enough PTH to allow for normal calcium homeostasis under basal
868
Clinical and laboratory observations
The Journal of Pediatrics December 1987
conditions but will not respond to a hypocalcemic stress. This parathyroid status theoretically may put our patient at risk for hypocalcemia during stress such as fever, which appears to precipitate hypocalcemia in patients with hypoparathyroidism/2 However, it is unclear whether there will be progressive and full recovery of the parathyroid glands or the "compensated" hypoparathyroid state is permanent. Only long-term evaluations can answer this question. REFERENCES
1. Fanconi A, Prader A. Transient congenital idiopathic hypoparathyroidism. Helv Paediatr Acta 1967;22:342-59. 2. Todt H, Eysold R, Korth G, Wunsche W. Transient hypoparathyroidism as a cause of spasms in the newborn. Padiatr Grenzgeb 1980;19:299-302. 3. Mallette L, Cooper J, Kirkland J. Transient congenital hypoparathyroidism: possible association with anomalies of the pulmonary valve. J PEDIATR 1982;101:928-3l. 4. Rosenbloom A. Transient congenital idiopathic hypoparathyroidism. South Med J 1973;66:666-70. 5. Mimouni F, Shaul P, Specker B, Tsang R. Magnesium (MG) infusion in preterm and term neonates: effects on calciotropic hormones and calcium (abstr). Pediatr Res 1986;20:415.
6. Drummond KN. In: Nelson WE, Behrman RE, Vaughn VC, eds. Nelson textbook of pediatrics, 12th ed. Philadelphia: WB Saunders, 1983:1307-14. 7. Tsang R, Chen I, McEnery P, et al. Parathyroid function tests with EDTA infusions in infancy and childhood. J PEDIATR 1976;88:250-6. 8. Sunderman FW Jr, Carroll JE. Measurements of serum calcium and magnesium by atomic absorption spectrometry. Am J Clin Pathol 1965;43:302-10. 9. Moore EW. Ionized calcium in normal serum, ultrafiltrates and whole blood, determined by ion-exchange electrodes. J Clin Invest 1970;49:318-34. 10. Dincsoy MY, Tsang RC, Laskarzewski P, et al. The role of postnatal age and magnesium on parathyroid hormone response during exchange blood transfusion in the newborn. J PEDIATR 1982;100:277-83. 11. Conley ME, Beckwith JB, Mancer JFK, Tenckhoff L. The spectrum of the DiGeorge syndrome. J PEDIATR1979;94:88390. 12. Halbert K, Tsang RC. Endocrine system. In: Gellis S, Kagan B, eds. Hypoparathyroidism: current pediatric therapy, 12th ed. Philadelphia: WB Saunders, 1983:306-8.
FELLOWSHIPS Available fellowships in pediatric subspecialties and those for general academic pediatric training are listed once a year, in May, in The Journal of Pediatrics. Each October, forms for listing such fellowships are sent to the Chairman of the Department of Pediatrics at most major hospitals in the United States and Canada. Should you desire to list fellowships, a separate application must be made each year for each position. All applications must be returned to The C. V. Mosby Company by February 15 of the listing year to ensure publication. Additional forms will be supplied on request from the Journal Editing Department, The C. V. Mosby Company, 11830 Westline Industrial Drive, St. Louis, M O 63146/314-872-8370.