Transient congenital hypoparathyroidism: Possible association with anomalies of the pulmonary valve

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December 1982 The J o u r n a l o f P E D I A T R I C S

Transient congenital hypoparat hyroidism : Possible association with anomalies of the pulmonary valve Transient congenital hypoparathyroidism was observed in four neonates who also had congenital cardiac defects. Severe hypocalcemia and hyperphosphatemia were noted at 2 or 3 weeks o f age, but resolved by 2 to 4 months o f age with minimal treatment (oral calcium alone). Parathyroid hormone, measured with a highly sensitive, homologous antiserum, was initially borderline detectable and became easily detectable as the hypocalcemia resolved. Immune function was normal in each patient. The congenital cardiac defects in each case involved the pulmonary valve. These patients might be regarded as having either a partial form o f the DiGeorge syndrome or a separate syndrome in which congenital pulmonary valve lesions are linked to delayed maturation o f parathyroid function by an as yet obscure mechanism.

Lawrence E. Mallette, James B. Cooper, and John L. Kirkland, Houston, Texas

CONGENITAL HYPOPARATHYROIDISM may be permanent or transient. ~,2 Rosenbloom 3 recently described two cases of transient congenital hypoparathyroidism and reviewed six other cases from the literature that he considered well documented. None of these patients had other congenital anomalies. Values were not obtained for immunoreactive parathyroid hormone (iPTH) in that report. By means of a new, homologous radioimmunoassay for PTH, we recently have documented the onset of parathyroid function in four such children. A cardiac defect was present in each patient, but immune function was normal. The findings in these four children will be contrasted with those in four other children seen during the same time period who had unequivocal evidence of the DiGeorge syndrome.

From the Divisions o f Endocrinology and Metabolism of the Departments o f Pediatrics and Medicine and the Division o f Allergy and Immunology, Department o f Pediatrics, Baylor College o f Medicine, and the Medical Service, Veterans Administration Medical Center. Supported by the Veterans Administration and by National Institutes o f Health grant A M 00811. Reprint address: Lawrence E. Mallette, Medical Service (l l lE), Veterans Administration Medical Center, 2002 Holcombe Blvd., Houston, TX 77211.

Vol. 101. No. 6. pp. 928-931

PATIENTS

AND METHODS

In the past two years, 12 children were evaluated in consultation for possible hypoparathyroidism. Eight children were suspected of having the DiGeorge syndrome and form the basis for this report. Three others had late onset of hypocalcemia (age 6 months or older), and one had congenital hypoparathyroidism with no other defect; these four cases will not be discussed further~ A clinical diagnosis of hypoparathyroidism was based on the presence of hypocalcemia and hyperphosphatemia unresponsive to d i e t a r y phosphate restriction in the absence of any other obvious cause for hypocalcemia. The DiGeorge syndrome was diagnosed when at least two of the following defects were present: severe hypoparathyroidism that persisted for six months or more, congenital cardiovascular anomalies involving the aorta or subclavian arteries, or defective T-cell number or function. The diagnosis of hypoparathyroidism was confirmed by the finding of low iPTH levels in serum despite the presence of hypocalcemia. The iPTH was measured with a new, highly sensitive radioimmunoassay for human PTH. The details of this assay have been reported. 4 Briefly, it employs an homologous antiserum, generated against human parathyroid hormone (hPTH) in a goat. The radioligand is a fragment of bovine PTH, [125I]bpTH(41-84). 5 The standard is a solution of hPTH extracted

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9 1982 The C. V. Mosby Co.

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Transient congenital hypothyroidism

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Table I. Four patients with DiGeorge syndrome Patient No.

Parathyroid tests Calcium

PO 4

iPTH

2

6.2 6.6

9.1 10.1

ND ND

3

5.4

10.4

ND

4

5.5

9.7

ND

1

Cardiovascular anomalies

Tetralogy of Fallot Right aortic arch with tracheovascular ring, anomalous right subclavian artery None at postmortem examination Normal clinical evaluation

T-cell nO.

Response to mitogen stimulation

Decreased Decreased

Decreased Normal

Decreased

Decreased

Decreased

Normal

ND = not detectable. Table II. Four patients with transient congenital hypoparathyroidism Parathyroid tests

PatientNo.

Calcium

P04

iPTH

Cardiovascular anomalies

5 6 7 8

5.5 4.7 5.6 6.5

7.1 12.7 8.2 8.5

32 57 50 44

Absent pulmonary valve syndrome Pulmonary stenosis, ASD, VSD Tetralogy of Fallot Pulmonary stenosis

T-cell no. mitogen response

Normal at 2 wk and 6 mo Normal at 1 and 5 mo Normal at 1 and 8 mo Not tested; no severe infections

ASD = atrial septal defect; VSD = ventricularseptal defect. from a human parathyroid adenoma, with values expressed in nanoliter equivalents (nleq) of this solution per milliliter of serum. The assay is specific for an antigenic site in the midregion of the PTH molecule (spanning amino acids 44 to 68). The normal range for children is up to 125 nleq/ml.6 The assay Can detect iPTH in serum of 93% of normal adults 4 or children.6 The iPTH is defined as detectable when (B/F)/(Bo/Fo) is less than 0.80 and as borderline detectable when (B/F)/(Bo/Fo) equals 0.80 to 0.85. 4 Bo/Fo is defined as the mean B / F value given by a reference panel of six to eight sera from adult patients with severe hypoparathyroidism (requiring at least 75,000 U of vitamin D daily). Mononuclear cell preparations were obtained by FicollHypaque separation from peripheral blood. The percentage of T-lymphocytes present was determined by sheep erythrocyte rosette formation2 In vitro lymphocyte response to stimulation with phytohemagglutinin, concanavalin A, and pokeweed mitogens was determined by [3H]-thymidine incorporation.8 RESULTS Of the eight children evaluated for suspected DiGeorge syndrome, the diagnosis was definitely established in four (Table I). Each had nondetectable iPTH at the initial evaluation, despite profound hypocalcemia. In two cases

later values were obtained during treatment with dihydrotachysterol and oral calcium supplements, and remained undetectable (Figure). Two of the four had congenital cardiovascular defects involving the aorta and/or subclavian artery, lesions typical of the DiGeorge syndrome.9 Patients 3 and 4 had normal clinical cardiac evaluation (electrocardiogram, chest radiograph, auscultation), and Patient 3 had normal cardiac findings at postmortem examination at age one year. Each child experienced repeated episodes of bacterial infection, and Patients 1 and 4 died suddenly at 2l and 12 months of age, respectively, during the onset of febrile illnesses. Patient 2 has survived to age 5 years, but has had repeated bacterial infections. He has normal lymphocyte responses to mitogen stimulation, despite lymphopenia and decreased T-cell numbers. His hypocalcemia was recognized only at age 5 years, but he had a lifelong history of stridor and tetanic "cramps." Other congenital anomalies were present in Patient 3 (high-arched palate, low-set ears) and Patient 4 (microphthalmia and micrognathia). These findings are typical of the DiGeorge syndrome. The second four patients had only some of the features of DiGeorge syndrome. Each had a congenital cardiac anomaly, but the hypoparathyroidism was transient and immune function normal (Table II). Each presented at 2 to 3 weeks of age with symptomatic hypocalcemia and

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Mallette, Cooper, and Kirkland

DIGEORGE

The Journal of Pediatrics December 1982

club foot, single kidney), Patient 6 (large ventral hernia), and Patient 7 (bilateral polydactyly).

TRANSIENT

150

DISCUSSION u.l.n.

100

E

\

------d.I.

50

m D

b.d.

I EARLY

LATE

EARLY

1 LATE

Figure. Immunoreactive PTH values in patients with the DiGeorge syndrome or with transient congenital hypoparathyroidism. Lines connect the initial values with those obtained one to four months later. The three broken lines indicate assay's limit of detection (d.l.), limit of borderline detection (b.d.), and upper limit of normal for children (u.l.n.).

hyperphosphatemia. Factors known to be associated with neonatal hypocalcemia, such as prematurity, respiratory distress syndrome, hyperbilirubinemia, placental abnormalities, and maternal diabetes or hypercalcemia) ~ were absent. In three of the four cases, the serum phosphate concentration was less elevated than in the patients with DiGeorge syndrome. The iPTH initially was in the borderline detectable range in each patient (Figure). These patients had a satisfactory response t o treatment with intravenous and oral calcium and did not require treatment with vitamin D congeners. After two to six months, serum calcium concentration remained normal without oral calcium supplements and iPTH was now easily detectable (Figure). The cardiac defect in each of these patients involved the pulmonary valve (Table II). One patient had tetralogy of Fa!lot, and a second had the absent pulmonary valve syndrome, a lesion with anatomy similar to that of the tetralogy.H The other two had pulmonary stenosis without anomalies of the great vessels. None of the four had immune defects. Three had normal T-cell studies on two occasions each, and the fourth has had no serious infections during the first year of life. Other congenital anomalies were noted in Patient 5 (cleft lip,

We have described four patients with transient congenital hypoparathyroidism. In these patients three clinical clues existed which, in retrospect, might have suggested the possibility that normal parathyroid function would eventually develop. First, the degree of hyperphosphatemia (in three of four cases) was less than in the patients with severe hypoparathyroidism. Second, these patients responded satisfactorily to oral calcium supplements alone. Patients with severe hypoparathyroidism can seldom be maintained without supplemental vitamin D. 12 One might speculate that the lower phosphate concentration and/or slight amount of PTH might have allowed formation of a greater amount of 1,25(OH)2D that might have promoted intestinal calcium absorption. The third clue was the borderline detectable iPTH value in each case. The studies of David and Anast! 3 showed that iPTH, although undetectable in a fairly large fraction of newborn infants, becomes easily detectable in the majority by 5 to 7 days of age. Furthermore, with the present assay almost all patients with parathyroid intact and with a serum calcium concentration below normal will have iPTH values above 125 nleq/ml) .6 Thus, the initial values in Patients 5 to 8 were depressed markedly. Their readings were not as low, however, as those of the reference panel of sera from adult patients with permanent severe hypoparathyroidism (see "Patients and methods"). Although the precision of any immunoassay is rather low in the range of ( B / F ) / ( B o / F o ) values above 0.80, the values from our patients were verified in two different assay runs, adding support for the interpretation that small amounts of iPTH were actually present. Likewise, the sera from the four patients with severe hypoparathyroidism reproducibly read with (B/ F ) / ( B o / F o ) values above 0.87; such discrimination would be possible with only a few PTH assays available today. The sensitivity of many assays is such that iPTH values in normal and hypoparathyroid subjects overlap greatly, and such low levels of iPTH would not be detected. TM The occurrence of cardiac lesions in patients with transient Congenital hypoParathyroidism does not appear to have been emphasized in the literature. None of the eight patients with transient Congenital hypoparathyroidism reviewed by Rosenbloom 3 was noted to have a cardiac anomaly. Conley et al 9 reviewed autopsy findings of five patients with features of the DiGeorge syndrome and mention that "several patients with hypocalcemia requiring treatment did have one or two normal appearing parathyroids." Their table lists four such hypocalcemic patients with congenital cardiac anomalies in whom both

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thymic and parathyroid tissue was demonstrated histologically. Clinical details such as the length and severity of hypocalcemia, iPTH levels, and number of infections were not given, however. It is not clear whether such patients should be considered to have a partial form of DiGeorge syndrome or a separate entity. One could consider the delayed appearance of parathyroid function to indicate parathyroid hypoplasia, rather than aplasia, analogous tO the thymic hypoplasia seen in some patients with DiGeorge syndrome. On the other hand, recovery of parathyro!d function leaves these patients with only their cardiac and somatic anomalies to suggest DiGeorge syndrome. At any rate, these patients are probably worthy of separate identification because of the better prognosis offered by the normal immunologic function and the fact that chronic treatment with vitamin D is not needed (and could even be harmful). The prognosis in fact would seem to depend mainly on the nature of the congenital cardiac anomaly. The strength of the association between pulmonary valve lesions and delayed maturation of parathyroid function is not clear at the present time. We did not have access to consecutive cases of congenital hypoparathYroidisml and there may have been a referral bias in our series toward those with cardiac lesions. Furthermore, the mechanism that might cause such as association is not evident. Further study will be necessary to determine the strength of this association and tO search for possible causes. REFERENCES 1. Root AW, and Harrison HE: Recent advances in calcium metabolism. II. Disorders of calcium homeostasis, J PEDIATR 88:177, 1976: 2. Macregor ME: Pediatric aspects of hypoparathyroidism,Proc R Soc Med 61:583, 1963.

Transient congenital hypothyroidism

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3. Rosenbloom AL: Transient congenital idiopathic hypoparathyroidism, South Med J 66:666, 1973. 4. Mallette LE, Tuma SN, Berger RE, and Kirkland JL: Radioimmunoassay for the middle region of human parathyroid hormone using an homologous antiserum with a carboxyterminal fragment of bovine parathyroid hormone as radioligand, J Ciin Endocrinol Metab 54:1017, 1982. 5. Mallette LE, and Bradley WA: Bovine parathyroid hormone (41-84), a hormone fragment with desirable properties for use as radioligand, J Lab Clin Med 98:886, 1981. 6. Mallette LE, Wilson D, and Kirkland JF: Evaluation of hypocaleemia using a highly sensitive midregion specific radioimmunoassay for human PTH, Pediatrics (in press). 7. Wybran J, Car MC, and Fundenberg HH: The human rosette-forming cell as a marker of a population of thymusdeprived cells, J CIin Invest 5"2537, 1972. 8. Eisen SA, Wedner HJ, and Parker CW: Isolation of pure human peripheral blood T lymphocytes using nylon wool columns, Immunol Commun 1:571, 1972. 9. ConleyME, Beckwith JB, Mancer JFK, and Tenckhoff: The spectrum Of the DiGeorge syndrome, J PEDIATR 94:883, 1979.

10. Anast CS: Tetany of the newborn, in Gardner LI, editor: Endocrine and genetic diseases of childhood and adolesence, Philadelphia, 1975, WB Saunders Company, p 377. 11. P!nsky WW, Nihill MR, Mullins CE, Harrison G, and McNamara DG: The absent pulmonary valve syndrome, considerations of management, Circulation 57:159, 1978. 12. Nagant deDeuxchaisnes C, and Krane SM: Hypoparathyroidism, in Avioli LV, and Krane SM, editors: Metabolic bone disease, New York, 1978, Academic Press, Inc, pp 217-445. 13. David L, and Anast CS: Calcium metabolism in newborn infants. The interrelationship of parathyroid function and calcium, magnesium and phosphorus metabolism in normal, "sick" and hypocalcemic newborns, J Clin Invest 54:287, 1974. t4. European PTH Study Group (EPSG): Interlaboratory comparison of radioimmunologicalparathyroid hormone determination, Eur J Clin Invest 8:149, 1978.