February 1977 TheJournalofPEDIATRICS
Neonatal primary hyperparathyroidism with autosomal dominant inheritance A l l e n M . S p i e g e l , M . D . , * Bethesda, Md., H a r o l d E. H a r r i s o n , M . D . ,
Baltimore, Md., S t e p h e n J. Marx, M.D., Edward M. Brown, M.D., and G e r a l d D. A u r b a c h , M . D . , Bethesda, Md.
PRIMARY HYPERPARATHYROIDISM in infancy is a rare and sometimes life-threatening disease. Prominent features of the 15 reported cases include anorexia, hypotonia, bony demineralization, hypercalcemia, and hyperplasia of the parathyroid. 1-~ Hillman and associates 1 reported two cases in brothers and termed the disease "neonatal familial primary hyperparathyroidism." Subsequently Goldbloom and associates-' described two sisters with similar findings and suggested that the disease was inherited as an autosomal recessive trait. In the process of testing a large kindred with familial hyperparathyroidism, we encountered a case o f severe neonatal hyperparathyroidism with features similar to those o f the 15 previously reported cases. This case indicates clearly that the disease may be inherited in autosomal dominant fashion. CASE REPORT Patient K.D., a female infant, was the product of an uncomplicated 43-week pregnancy and weighed 3.3 kg at birth. On initial physical examination, a very narrow chest, a high-pitched cry, hypotonia, and an anal fissure were noted which prompted a roentgen survey to determine if other anomalies were present. Generalized bony demineralization was seen, as well as subperiosteal resorption of the long bones, multiple rib fractures, and irregular destruction of the femoral and humeral metaphyses. With these findings and the development of respiratory distress, the infant was transferred to Baltimore City Hospital on the second day of life. The striking feature on examination was the
From the Metabolic Diseases Branch, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, and Department of Pediatrics, Baltimore City Hospital *Reprint address: Bldg. 10, Room 9D-20, National Institutes of Health, Bethesda, MD 20014.
extremely narrow chest similar to that found in Jeune asphyxiating thoracic dystrophy. The tachypnea and dyspnea were thought to be due to the abnormalities of the rib cage resulting from the marked demineralization. Laboratory data at age two days included a serum calcium concentration of 13.9 mg/dl (64% ionized), phosphorus of 3.4 mg/dl, alkaline phosphatase of 30.2 Bodansky units, and immunoreactive parathyroid hormone plasma concentration of 2.3 ng/ml.* The mother's serum calcium concentration was 9.2 mg/ dl and phosphorus 3.7 mg/dl. A diagnosis of neonatal primary hyperparathyroidism was made. Two weeks after birth, total parathyroidectomy was performed. Diffuse hyperplasia (initially interpreted as clear-cell, but after electron microscopic study thought to be "light-chief-cell"0 was noted in each of the parathyroid glands. Serum calcium and phosphorus concentrations postoperatively at age 29 days were 7.3 and 4.0 mg/dl, respectively, and therapy with dihydrotachysterol and calcium lactate was instituted. Roentgen studies six months after discharge showed significant remineralization of bone. The child has now been observed for three years and eight months since operation. The bones have completely remineralized, and there are no obvious skeletal deformities. She is growing along the tenth percentile for height and twenty-fifth percentile for weight. She has been managed with dihydrotachysterol between 0.125 and 0.25 mg/day and 550 mg of calcium gluconate daily by mouth. Serum calcium concentrations have been maintained above 9.0 mg/dl and she has been symptom free. There are marked dental caries, owing to poor enamel mineralization. FAMILY
Patient K.D. is a m e m b e r of the N kindred (Fig. 1 and Table I). Her father, H.D., was found to be hypercalcemic *This determination was done for us by Dr. Criraud Foster, Department of Physiology,Johns Hopkins University,Schoolof Medicine. The result is four to five times the upper limit of normal in this laboratory.
VoL 90, No. 2, pp. 269-272
Spiegel et al.
The Journal of Pediatrics February 1977
Nots . . . . . . . ,
Fig. 1. Pedigree of N. kindred showing autosomal dominant inheritance. Subjects with definite hypercalcemia are listed in Table I by generation sequentially from left to right.
in the course of screening asymptomatic members of the family of B.N., the index case. Definite hypercalcemia (Table I) has been found in 15 family members (including six under the age of 16) out of a total 31 screened; five additional family members had serum calcium determinations at the upper limits of normal (10.0 to 10.6 mg/dl). Serum phosphate concentrations in these 15 family members were either frankly depressed or low normal. Urinary cyclic adenosine monophosphate excretion, an index of PTH activity7 was elevated in 6 of 15. Extensive evaluation for other endocrine disease has revealed no evidence of multiple endocrine neoplasia Types I or II, ~ although three family members have Hashimoto thyroiditis. Exploration of the neck has been performed in five family members in addition to Patient K.D. All five remain hypercalcemic including two operated on at the National Institutes of Health with removal of 3-1/2 parathyroid glands from each. The glands removed varied in weight from normal ( ~ 5 0 mg) up to 1.5 gm. Pathologic examination disclosed chief-cell hyperplasia of the parathyroids in each case. DISCUSSION Hyperparathyroidism occurs rarely in the neonatal period. Several cases have been reported in which infants born to mothers with untreated hypoparathyroidism have had bone changes on roentgen examination consistent with hyperparathyroidism? This has been ascribed to
secondary hyperplasia of the fetal parathyroids. In our patient's mother, serum calcium and phosphate concentrations were normal, and there was no history of hypoparathyroidism. Since 1939, a total of 15 cases of primary hyperparathyroidism in infancy has been reported. The disease has been characterized clinically by hypotonia, poor feeding, constipation, and respiratory distress. Marked hypercalcemia, hypophosphatemia, and severe bony demineralization, but not nephrocalcinosis, have been observed in these cases. Histologic evaluation of the parathyroids at postmortem examination or surgery has shown hyperplasia with the cell type variously referred to as clear-cell or vacuolated chief-cell. Our patient closely fits this pattern. The etiology of neonatal primary hyperparathyroidism is not known. Two separate reports of the disease occurring in siblings, however, have prompted the suggestion that the parathyroid abnormality is inherited." '-' Both Hillman and associates I and Goldbloom and associates2 have stated that the inheritance is autosomal recessive. Serum calcium and phosphate concentrations were normal in both parents of Hillman's cases and Goldbloom's cases. Laboratory evaluation of parents has been reported for only one other case and in that instance they too were normal. In two separate cases parental consanguinity (first cousin) has been found. 1 :' In our patient, however, an autosomal dominant pattern of inheritance is clear (Fig. 1). The evidence for autosomal recessive
Primary hyperparathyroidism with autosomal dominant inheritance
Table I. Members of N. kindred with definite hypercalcemia
Urinary Age at Calcium I Phosphorous cyclicAMP Generation Patient diagnosis (mg/ dl) (mg/ dl) (~tmot/gm creatinine) I
M.M. J.D. A.B.
64 61 54
12.2 12.0 13.7
2.2 1.9 2.1
6.3 2.6 7.0
I.C. B.N. H.D. R.D. R.Di.
45 43 22 28 30
11.9 11.3 12.5 13.1 11.9
2.9 2.9 1.8 1.9 3.0
6.5 4.3 1.8 0.5 1.4
W.B. B.S. N.N. K.D.
16 25 15 Neonatal
13.0 12.1 12.1 13.9
2.8 3.0 3.1 3.4
5.5 2.2 3.3~ N.D.
D.D. S.Di. W.Di.
3 10 5
13.6 12.6 12.2
3.1 3.1 3.2
N.D. 3.5 5.9
Symptoms Nephrolithiasis None Chondrocalcinosis + pseudogout Peptic ulcer None None None None (first child had neonatal tetany) None None None Bone disease (see case report) Growth retardation None None
Chief cell hyperplasia
Chief cell hyperplasia
Chief cell hyperplasia Chief cell hyperplgsia
Chief cell hyperplasia Chief cell hyperplasia
Normal range (adults): calcium 8.6-10.6;phosphorous 2.4-5.0; urinary cyclicadenosine monophosphate 1.3-4.1.' *Not explored. "fNot done. inheritance in the other reported cases is not conclusive. Normal serum calcium and phosphate concentrations in the parents of affected infants does not rule out autosomal d o m i n a n t inheritance, since variable penetrance can occur. Extensive family screening was not described in any of the previous reports. We may, on the other hand, be dealing with a phenotypically similar disease with at lease two distinct patterns of inheritance. Two other points deserve comment. The n u m b e r of children with hypercalcemia in the N kindred is striking. Unlike Patient K.D., the other affected children have been asymptomatic; their disease was discovered only in the course of family screening. (One possible exception is D.D., a 3-year-old who does not show bony changes or characteristic symptoms of hypercalcemia, but has had retarded growth.) This suggests that hyperparathyroidism in the pediatric age group may be more c o m m o n than currently appreciated. The important question of whether surgery is routinely indicated in such cases is unresolved. The second point relates to the type of surgery performed in neonatal primary hyperparathyroidism. Seven of the 15 reported cases died without surgery and two died postoperatively; in the five surgical survivors, three required re-exploration after initial subtotal parathyroidectomy failed to correct hypercalcemia. For this reason, the initial treatment in our case was total parathy-
roidectomy. Unfortunately, total parathyroidectomy necessitates permanent treatment with vitamin D and the attendant danger of renal damage secondary to vitamin D excess. With close follow-up our patient has been asymptomatic; but on one occasion hypercalcemia occurred and resolved following reduction of dihydrotachysterol dosage. The practical implications of our findings in this case are clear. Neonatal primary hyperparathyroidism, although rare, may be fatal if not promptly recognized and surgically corrected. Since this disease may occur in the setting of familial hyperparathyroidism with autosomal dominant inheritance, infants of affected family members should be tested early in neonatal life and periodically thereafter. Dr. Alex Haller performed the surgery on this patient. We thank Mrs. L. Perry for expert secretarial assistance. REFERENCES
1. Hillman DA, Scrivner CR, Pedvis S, et al: Neonatal familial primary hyperparathyroidism, N Engl J Med 270:483, 1964. 2. Goldbloom RM, Gillis DA, and Prasad M: Hereditary parathyroid hyperplasia a surgical emergency of early infancy, Pediatrics 49:514, 1972. 3. Corbeel L, Casaer P, Malvaux P, et al: Congenital hyperparathyroidism, Arch Fr Pediatr 25:879, 1968. 4. Bradford WD, Wilson JW, and Gaede JT: Primary neonatal
Spiegel et al.
hyperparathyroidism, an unusual cause of failure to thrive, Am J Clin Pathol 59:267, 1973. 5. Rhone DP: Primary neonatal hyperparathyroidism, Am J Ctin Pa~hol 64:488. 1975. 6. Garcia-Bunuel R, Kutchemeshgi A, and Brandes D.: Hereditary hyperparathyroidism: The fine structure of the parathyroid gland, Arch Pathol 97:399, 1974. 7. Mallette LE, Bilezikian JP, Heath DA, and Aurbach GD:
The Journal Of Pediatrics February 1977
Primary hyperparathyroidism: Clinical and biochemical features, Medicine 53:127, 1974. 8. Marx SJ, Spiegel AM, Brown EM, and Aurbach GD: Family studies in patients with primary parathyroid hyperplasia, submitted to Am J Med (in press). 9. Bronsky D, Kaimko RT, Moncada R, et al: Intrauterine hyperparathyroidism secondary to maternal hypoparathyroidism, Pediatrics 42:606, 1968.