* Correspondence author;

Address: Children Hospital, Sheshgelan Ave, Tabriz,IR Iran

E-mail: shivasiamak@yahoo.com

Severe Neonatal Hypercalcemia due to Primary

Hyperparathyroidism; A Case Report

Siamak Shiva*1, MD, Pediatric Endocrinologist; Alireza Nikzad1, MD, General Physician;

Saeid Aslanabadi2, Pediatric Surgeon; Vahid Montazeri3, MD, Thoracic surgeon;

Mohammad-Reza Nikzad1, MD, General Physician

1. Department of Pediatrics, Tabriz University of Medical Sciences, IR Iran

2. Department of Pediatric Surgery, Tabriz University of Medical Sciences, IR Iran

3. Department of Thoracic Surgery, Tabriz University of Medical Sciences, IR Iran

Received: 25/01/08; Revised: 22/05/08; Accepted: 06/06/08

Abstract

Background: Neonatal primary hyperparathyroidism (NPHP) is a rare disease characterized by

marked hypercalcemia, diffuse parathyroid hyperplasia and skeletal demineralization. These

patients have symptoms of chronic hypercalcemia such as failure to thrive, irritability,

abdominal pain and anorexia. It is often fatal unless parathyroidectomy is performed.

Treatment with drugs usually is inadequate and often results in chronic hypercalcemia and

death.

Case presentation: A 10-day-old, 2.9 kg male newborn was hospitalized for anorexia, poor

feeding, cyanosis, hypotonia, lethargy and severe dehydration. Diagnosis of severe

hypercalcemia due to primary hyperparathyroidism was established and surgical approach

selected because of failure of medical therapy to control hypercalcemia. The baby was

successfully treated by total parathyroidectomy with autotransplantation.

Conclusion: Although neonatal primary hyperparathyroidism (NPHP) is a rare disease, it must

be considered for differential diagnosis in neonates with severe hypercalcemia. Early diagnosis

and total parathyroidectomy with autotransplantation can be life-saving.

Key Words: Primary hyperparathyroidism; Neonate; Parathyroidectomy; Autotransplantation

Introduction

Neonatal primary hyperparathyroidism

(NPHP) is a rare disease that presents in the

first 6 months of life[1]. It is almost invariably

fatal unless a prompt diagnosis is made and

urgent surgical intervention instituted[2]. It is

associated with hypotonia, respiratory

distress, irritability, lethargy, failure to thrive,

constipation and severe hypercalcemia with

Case Report Iran J Pediatr

Sep 2008; Vol 18 ( �o 3), Pp:277-280

278 Neonatal Hypercalcemia due to Primary Hyperparathyroidism; S Shiva, et al

elevated parathyroid hormone (PTH) levels[1].

Radiographs show severe bone

demineralization[1,3]. The etiology is genetic[4]

and results from inactivating mutation of

calcium sensing receptor gene, in which the

inhibitory effect of extracellular calcium on the

secretion of PTH by chief cell is absent[1]. All

reported cases of NPHP have been due to

parathyroid chief cell hyperplasia[1-6].

Surgical treatment with subtotal parathyro-

idectomy, total parathyroidectomy or total

parathyroidectomy with autotransplantation,

is preferred modality. The mortality rate with

this modality is 24%[7]. About 50 neonates with

NPHP have been reported and it has been

suggested as a possible contributor to a small

number of cases of the Sudden Infant Death

Syndrome[2,4]. The authors report on a case

presenting in a male neonate, review the world

literature and discuss the clinical

manifestations, investigators' findings and the

management options available.

Case Presentation

A 10-day-old 2.9 kg male newborn was

hospitalized for anorexia, poor feeding,

cyanosis, hypotonia, lethargy and severe

dehydration. He was a full term baby at birth

weighing 3400 grams and his parents were

related (cousins). Despite rehydration, he had

hypercalcemia with Ca concentration of 18.2

mg/dl (normal, 8.6 to 10.3). Other laboratory

findings were serum PTH level of 996 pg/ml

(Normal, 7 to 82), phosphorus level of 1.6

mg/dl (Normal, 4 to 6.5) and alkaline

phosphatase level of 1322 IU/L (Normal, 180

to 1200). Urine Ca excretion was 12 mg/kg/d.

Evaluation of mother for serum levels of Ca, P

and PTH showed normal values. With

vigorous medical management using saline

diuresis, furosemide, hydrocortisone and

intravenous pamidronate 1mg/kg/d for 3

days, serum Ca level remained between 13-15

mg/dl. Full skeletal survey revealed severe

and generalized osteopenia. Bone density was

diffusely decreased and multiple regions of

pathologic fractures in proximal and distal

parts of femur, humerus and ribs along with

lung calcification were seen (Fig 1).

Fig 1- Skeletal survey of patient, demonstrating

multiple fractures and generalized osteopenia

Ultrasound revealed medullary nephro-

calcinosis; echocardiography was normal.

99M-TC-sestaMIBI scan showed homogeneous

uptake of the radiotracer in parathyroid

glands with no evidence of parathyroid

adenoma. Combination of clinical, laboratory

and radiological findings were consistent with

the diagnosis of NPHP. Since patient did not

respond to the medical therapy and his

symptoms persisted, surgical approach was

considered. We performed total parathyroid-

ectomy with autotransplantation. After

removing all 4 parathyroid glands, a portion of

a gland was autotransplanted in

sternocleidomastoid muscle. Because of

hypocalcemia (serum Ca 7.5 mg/dl) we

started calcium supplementation and vitamin

D therapy during the second day after surgery.

Two months after surgery patient was

eucalcemic and had no need for vitamin D

supplementation. Histological examination of

parathyroid glands revealed diffuse chief cell

hyperplasia (Fig 2).

279 Iran J Pediatr, Vol 18 (�o 3); Sep 2008

Fig 2- Microphotograph of parathyroid tissue

shows diffused chief cell hyperplasia. Note the

uniform appearance of parathyroid chief cells

(hematoxylin & eosin stained)

Discussion

Neonatal primary hyperparathyroidism

(NPHP) is a rare disease, which is often fatal.

This condition results from chief cell

hyperplasia and excessive secretion of PTH[3-

6]. Usually symptoms manifest in the first days

after birth[4]. Symptoms include poor feeding,

irritability, constipation, polyuria, hypotonia,

respiratory distress and bone abnormality

such as osteopenia, subperiosteal bone

resorption, pathologic fracture and failure to

thrive almost in all cases[4,5]. NPHP is

characterized by marked hypercalcemia,

hypophosphatemia, hyper-phosphaturia,

hypercalciuria and elevated PTH level[3,4]. In

differential diagnosis other causes of

hypercalcemia should be considered

including: iatrogenic hypercalcemia (calcium

salts), idiopathic infantile hypercalcemia,

Williams syndrome, vitamin D intoxication

and familial hypocalciuric hypercalcemia

(FHH). FHH manifests with elevated serum

levels of calcium and magnesium. Patients

with this disease have normal phosphate and

calcitriol levels with no hypercalciuria.

PTH level could be normal or mildly

elevated[3-5]. Hypercalcemia lasts life-long;

patients have no other problems[5]. Most

patients do not require any treatment. In

contrast, NPHP can be life-threatening if left

untreated[1]. Mutations in the calcium-sensing

receptor (CASR) gene which lead to loss of

normal function of these receptors can be seen

in both FHH and NPHP. Activation of CASR by

extracellular calcium inhibits secretion of PTH

by the chief cells[1,9]. In NPHP, medical therapy

is inadequate and surgical modality should be

considered[3-5]. This intervention must be

undertaken immediately to avoid death or

irreversible long term complications such as

nephrocalcinosis, cardiac abnormalities, bone

resorption, or central nervous system

alterations[4].

As in our case many other reports show

that the treatment of choice is total parathyro-

idectomy with autotransplantation[4,10-13].

Without parathyroidectomy, affected infants

will usually die by the age of three months[10].

Medical therapy without surgical intervention

has a mortality rate of 70% to 87% and severe

long term complications in the survivors[4].

Ross et al reported that seven of eight patients

treated medically for primary hyperpara-

thyroidism died in infancy, with a mortality

rate of 87.5% and the mortality rate among

patients treated surgically was reduced to

24%[7]. Meeran et al reported a case with

NPHP who survived without parathyroid-

ectomy to an age of nine months, in whom no

fractures were observed and the hyper-

calcaemia became masked by vitamin D

deficiency[10]. These patients are critically ill at

presentation and initial therapy with

hydration, furosemide, steroids, and intra-

venous pamidronate are not enough to control

hypercalcemia completely[11,14].

Despite the intensive medical therapy it

was not easy to prepare the severely ill patient

for parathyroidectomy. Three possible

surgical procedures for these patients are:

total parathyroidectomy, subtotal parathyro-

idectomy or total parathyroidectomy with

autotransplantation. Total parathyroidectomy

leads to hypoparathyroidism with a life-long

need to calcium and vitamin D supple-

mentation. In total parathyroidectomy with

autotransplanttation all 4 parathyroid glands

are removed and a small portion of a gland is

implanted into intramuscular pockets[1-5,8].

280 Neonatal Hypercalcemia due to Primary Hyperparathyroidism; S Shiva, et al

Excellent results obtained in our patient

demonstrate that total parathyroidectomy

with autotransplantation could successfully

regulate calcium homeostasis in severe

primary hyperparathyroidism. However, we

should not forget that hypercalcemia may

recur in this patient in the future.

Conclusion

Although NPHP is a rare disease, it must be

considered for differential diagnosis in

neonates with severe hypercalcemia. Early

diagnosis and total parathyroidectomy with

autotransplantation can be life-saving.

References

1. Doria AS, Huang C, Makitie O, et al.

Neonatal, severe primary hyperpara-

thyroidism: a 7-year clinical and

radiological follow-up of one patient.

Pediatr Radiol. 2002;32:684-9.

2. Blair JW, Carachi R. Neonatal primary

hyperparathyroidism - a case report and

review of the literature. Eur J Pediatr

Surg. 1991;1(2):110-4.

3. Rodd C, Goodyer P. Hypercalcemia of the

newborn: etiology, evaluation, and

management. Pediatr Nephrol. 1999;

13(6):542-7.

4. Janik JE, Bloch CA, Janik JS. Intrathyroid

parathyroid gland and neonatal primary

hyperparathyroidism. J Pediatr Surg.

2000;35(10):1517-9.

5. Payne MS, Suskind DL, Vargas A, et al.

Parathyroid hyperplasia: an unusual

cause of neonatal hypercalcemia. Int J

Pediatr Otorhi. 2001;61(3):253-7.

6. Gabbett MT, Jones K, Cowell CT, et al.

Neonatal severe hyperparathyroidism:

an important clue to the aetiology. J

Paediatr Child H. 2006;42(12):813-6.

7. Ross AJ, Cooper A, Attie MF, et al.

Primary hyperparathyroidism in infancy.

J Pediatr Surg. 1986;21(6):493-9.

8. Cakmak O, Agis ER, Tezic T, et al.

Primary hyperparathyroidism in infancy:

A case report. J Pediatr Surg

1996;31(3):437-8.

9. Cole DEC, Janicic N, Salisbury SR, et al.

Neonatal severe hyperpara-thyroidism,

secondary hyperparathyro-idism, and

familial hypocalciuric hypercalcemia:

Multiple different phenotypes associated

with an inactivating Alu insertion

mutation of the calcium-sensing receptor

gene. Am J Med Genet. 1998;71(2):202-

10.

10. Meeran K, Husain M, Puccini M, et al.

Neonatal primary hyperparathyroidism

masked by vitamine D deficiency. Clin

Endocrinol. 1994;41(4):531-4.

11. Fox L, Sadowsky J, Pringle KP, et al.

Neonatal hyperparathyroidism and

pamidronate in an extremely premature

infant. Pediatr. 2007;120(5):1350-4.

12. Luts P, Kane O, Pfersdorff A, et al.

Neonatal primary hyperparathyroidism:

Total parathyroidectomy with auto-

transplantation of cryopreserved para-

thyroid tissue. Acta Pediatrica.

1986;75(1):179-82.

13. Al Shaikh HA, Bappal B, Nair R, Al

Khusaiby S. Spontaneous improvement

of severe neonatal hyperparathyroidism

after failed total parathyroidectomy.

Indian Pediatr. 2003;40(3):255-7.

14. Darcan S, Coker M, Aydinok Y, et al.

Persistent elevated serum levels of intact

parathyroid hormone after reoperation

for primary hyperparathyroidism and

after pamidronate therapy. Turkish J

Pediatr. 2003;45(3):269-72.