Published online November 1, 2007
PEDIATRICS Vol. 120 No. 5 November 2007, pp. e1350-e1354 (doi:10.1542/peds.2006-3209)
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EXPERIENCE & REASON

Neonatal Hyperparathyroidism and Pamidronate Therapy in an Extremely Premature Infant

Lisa Fox, MB, ChB, FRACPa, Joel Sadowsky, MB, ChB, FRACPa, Kevin P. Pringle, MB, ChB, FRACSa,b,c, Alexa Kidd, MBBS, MRCP, MScd, Jean Murdoch, MD, FRCP(C)e, David E.C. Cole, MD, PhD, FRCPCf and Esko Wiltshire, MD, FRACPa,d,g

a Departments of Paediatrics and Child Health
e Radiology
d Central Regional Genetics Service, Wellington Hospital, Capital and Coast District Health Board, Wellington, New Zealand; Departments of
b Surgery
c Obstetrics and Gynaecology
g Paediatrics and Child Health, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand
f Departments of Laboratory Medicine and Pathobiology, Medicine, and Pediatrics, University of Toronto, Toronto, Ontario, Canada

ABSTRACT

We describe the use of pamidronate to control marked hypercalcemia in an extremely premature infant with neonatal hyperparathyroidism that resulted from an inactivating mutation (R220W) of the calcium-sensing receptor. Despite improvement in bone mineralization and subsequent parathyroidectomy with normalization of the serum calcium level, the combination of chronic lung disease, osteomalacia, and poor thoracic cage growth ultimately proved fatal. Pamidronate therapy seems to be safe in the short-term and effective in helping control hypercalcemia even in the very premature infant, allowing for planned surgical intervention when it becomes feasible.

Key Words: neonate • bisphosphonate • hypercalcemia • calcium-sensing receptor • familial hypocalciuric hypercalcemia • neonatal hyperparathyroidism

Abbreviations: NHPT, neonatal hyperparathyroidism • CaSR, calcium-sensing receptor • NSHPT, neonatal severe hyperparathyroidism • FHH, familial hypocalciuric hypercalcemia • PTH, parathyroid hormone • CGA, corrected gestational age

eonatal hyperparathyroidism (NHPT) is a rare disorder that can be caused by loss-of-function mutations in the calcium-sensing receptor (CaSR). Most reported cases have been of term infants1–4; there has been 1 report of an affected premature infant5 but no reports of extremely premature infants. Total parathyroidectomy may be life saving for severely affected infants,3,4 although novel medical therapies are being investigated. A recent report has demonstrated the effectiveness of bisphosphonate (pamidronate) therapy in reversing severe hypercalcemia in term infants with recessive neonatal severe hyperparathyroidism (NSHPT), which allows parathyroidectomy to be delayed until the infant is clinically stable.2

The CaSR establishes the "set point" for calcium homeostasis. Loss-of-function mutations lead to a higher set point for serum calcium level and cause a spectrum of disease including (1) the most severe form (NSHPT), with life-threatening hypercalcemia and bone disease secondary to demineralization,6 (2) NHPT with moderate hypercalcemia and hyperparathyroid bone disease, and (3) familial hypocalciuric hypercalcemia (FHH), which is a relatively benign autosomal-dominant disorder with asymptomatic hypercalcemia.3–5,7,8

Bisphosphonates have been used in neonates with hypercalcemia caused by subcutaneous fat necrosis9 and with osteogenesis imperfecta,10,11 but we could find no reports of use of these agents in premature infants. Here we report an extremely premature infant with NHPT and severe bone disease, outline the difficulties in management, and describe the safe short-term use of pamidronate at early gestation.

PATIENT REPORT AND METHODS

The patient, a girl, is the first child of healthy, nonconsanguineous parents and was delivered by emergency cesarean section at a gestational age of 27 weeks 4 days after an acute antepartum hemorrhage. One dose of betamethasone was administered before delivery. Her birth weight was 1230 g (90th centile), head circumference was 27.6 cm (97th centile), and birth length was 37 cm (90th centile). She was intubated at delivery and given surfactant. The initial chest radiograph (Fig 1) showed skeletal changes consistent with hyperparathyroidism and pulmonary changes consistent with respiratory distress syndrome. A family history of FHH included the paternal grandmother, and several members of the paternal family underwent parathyroidectomy as adults. The patient's mother had a serum total calcium level (corrected for albumin) of 2.5 mmol/L (adult reference range: 2.25–2.50 mmol/L), serum phosphate level of 1.38 mmol/L (reference range: 0.95–1.60 mmol/L), and parathyroid hormone (PTH) level of 1.3 pmol/L (reference: <6 pmol/L). However, the patient's father had a corrected calcium level of 3.06 mmol/L, serum phosphate level of 0.87 mmol/L, and PTH level of 2.7 pmol/L, a fact that had not been recognized previously.


Figure 1
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  		FIGURE 1 Chest radiograph on day 1 demonstrating short ribs with anterior rib fractures, significant osteopenia outside the normal appearance for gestation, and subperiosteal resorption of bone, intracortical tunneling, and poor definition of trabeculae (as classically observed in hyperparathyroidism). Lung fields are small. The diffuse, slightly coarse infiltrate present throughout with areas of punctate lucencies suggests early pulmonary interstitial emphysema on a background of pulmonary hypoplasia and mild respiratory distress syndrome.

 
Hypercalcemia was first noted at 15 hours of age, with total a corrected serum calcium level of 3.08 mmol/L (neonatal reference range: 2.25–2.70 mmol/L), phosphate level of 2.05 mmol/L (reference range: 1.55–2.65 mmol/L), alkaline phosphatase level of 203 U/L (reference range: 0–400 U/L), PTH level of 233 pmol/L (reference: <6 pmol/L), urine calcium/creatinine ratio of 1.33 (reference: <1.96 mmol/mmol in infancy), and 25-hydroxyvitamin D level of 15.3 µg/L (18–56 µg/L, day 2).

Treatment and Progress
The patient's hypercalcemia was managed initially with hyperhydration, frusemide, and steroids, with minimal effect. She also received treatment with 400 IU of vitamin D daily. On day 7, treatment with intravenous pamidronate (20 mg/m2) was initiated. Six doses of 20 to 30 mg/m2 were given over the next 6 weeks with the aim of performing parathyroidectomy once it was technically feasible and she was clinically stable. Pamidronate was given in 5% (wt/vol) dextrose over 4 hours with a maximum concentration of 240 µg/mL. Her serum calcium level reduced significantly, by 7% to 28%, with each dose (Fig 2).


Figure 2
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  		FIGURE 2 Effect of treatment on calcium and PTH. A, Change in PTH over time (the reference interval [<6 pmol/L] is shaded). B, Change in serum calcium (the reference interval is shown with lighter shading). Pamidronate infusions (20 or 30 mg/m2) are indicated by gray bars, and the parathyroidectomies (days 55 and 105) are indicated by arrows.

 
The radiographic appearances initially worsened, with a visible increase in subperiosteal bone resorption and intracortical tunneling. A skull radiograph taken on day-of-life 10 is shown in Fig 3. Improvement in radiographic bone density was noted 2 weeks after the first pamidronate infusion, with evidence of healing of femoral metaphyseal fractures at 1 month (2 infusions given) and subperiosteal resorption of bone subsequently resolved. There was significant periosteal reaction along the long tubular bones, with increased density and thickness, from 7 weeks of age (when 5 infusions had been given), which is earlier than usually seen for physiologic periosteal reaction of the newborn (as demonstrated in Fig 4). Radiographs were reviewed by 2 radiologists, each with >10 years' experience in neonatal radiograph interpretation at a tertiary-level neonatal unit.


Figure 3
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  		FIGURE 3 Lateral skull radiograph of our patient at 10 days of life, which demonstrates severe granular rarefaction of the skull, with increased prominence of the semicircular canals, resorption of the inner table of the skull, and complete resorption of the lamina dura around the teeth.

 

Figure 4
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  		FIGURE 4 Chest radiograph of our patient at 19 weeks of age, which demonstrates significantly increased bone density with very mature periosteal reaction around the ribs and upper humeri.

 
We did not observe any immediate adverse effects from the pamidronate; specifically, there was no hypomagnesemia, vomiting, or lymphocytopenia, no evidence of a febrile reaction with the first dose, and no respiratory distress associated with infusion, as is seen occasionally in infants with osteogenesis imperfecta.11

Parathyroidectomy was performed at 8 weeks of age (corrected gestational age [CGA]: 35 weeks). Globular collections of brown fat appeared very similar to neonatal parathyroid tissue. Four (of 9) pieces of excised tissue were confirmed histologically to be hyperplastic parathyroid tissue. Her calcium and PTH levels decreased initially but rose to previous levels within 48 hours. Repeat surgical exploration at 42 weeks' CGA removed a fifth parathyroid gland, which resulted in rapid and permanent reduction in her calcium and PTH levels (Fig 2). Supplemental calcium (up to 1.7 mmol every 6 hours and calcitriol (0.25 µg daily) were given to prevent symptomatic hypocalcemia.

Despite pamidronate treatment, growth of her thorax was poor. She developed progressive thoracic deformity, limb fractures, and severe chronic lung disease. She was unable to sustain adequate respiratory function without ventilator support for >24 hours. At 5 months of age, bronchoscopy demonstrated tracheomalacia, and a thoracic computed tomography scan showed areas of hyperinflation and atelectasis consistent with chronic lung disease. Given her poor respiratory prognosis, intensive care was withdrawn at 5.5 months of age (CGA: 9 weeks postterm) and she died as a result of respiratory failure.

Molecular Analysis
Genomic DNA was extracted from leukocytes, the entire coding sequence of the CaSR gene (including the intron-exon splice junctions) was amplified by polymerase chain reaction, and the amplicons were subjected to denaturing high-performance liquid chromatography (dHPLC) to identify heterozygosity.12,13 To ensure that there were no mutations with homoallelic homozygosity, each fragment was mixed with an equal amount of amplified control DNA, heated to 95°C, and allowed to reanneal and form heteroduplexes. dHPLC analysis identified heterozygosity in exon 4, and bidirectional sequencing confirmed a single C-to-T transition at nucleotide position 658, which predicts heterozygosity for an R220W missense mutation. Search of the Calcium Sensing Receptor Database (available at www.casrdb.mcgill.ca) revealed that this mutation had been reported previously in 3 other families.14–16

DISCUSSION

To our knowledge, this is the first report of NHPT and use of pamidronate in an extremely preterm infant. In its most severe form, NSHPT, this disease presents with failure to thrive, lethargy, poor feeding, ileus, and hypotonia. Rapid progression of skeletal demineralization leads to multiple fractures and thoracic deformities.17 The mortality rate has been reported at up to 50% in some series, because of severe hypercalcemia, respiratory failure secondary to thoracic deformation, and/or respiratory infection.18 In survivors, neuropsychological development may also be significantly affected.19,20

In NHPT in a term infant, the hypercalcemia is less severe, as is the bone disease. However, our extremely premature patient had a skeletal phenotype that more closely resembled that seen in NSHPT despite control of hypercalcemia with pamidronate infusions. Whether this is related to the specific genotype or also reflects interplay with external exacerbating factors deserves comment. Inactivating CaSR mutations cause a wide spectrum of disease that ranges from stillbirth and life-threatening neonatal disease to neonatal skeletal demineralization that resolves with time and even to entirely asymptomatic FHH.4,21,22 Within our patient's family, there was no history of NHPT, but several adults had undergone parathyroidectomy for symptomatic hypercalcemia and elevated serum PTH concentrations, suggesting a more severe phenotype than seen in many other families with FHH. Molecular analysis of CaSR revealed a heterozygous R220W mutation, previously associated with FHH14–16 and NHPT.15 The substitution of the arginine at position 220 by tryptophan occurs in the portion of the amino-terminal extracellular domain of the CASR protein that putatively participates in calcium binding. In attempting to explain the occurrence of NHPT in their patient, Schwarz et al15 suggested that R220W interrupts ligand binding and exerts a dominant-negative effect, as has been the case in other mutations.23 Using a transiently infected human embryonic kidney (HEK) cell-culture system to explore the functional properties of this mutation, D'Souza-Li et al16 found that the R220W mutant has a right-shifted calcium-response curve and a calcium set-point concentration that is more than threefold higher than that in controls (15.4 ± 0.5 vs 4.0 ± 0.1 mmol/L) but is expressed normally at the cell surface. Additional functional studies are needed. The CaSR is expressed in the placenta. In mice, inactivating mutations in the CaSR reduce transfer of calcium to the developing fetus.24 A similar effect in humans would add to skeletal demineralization (by further increasing fetal PTH release).

Whatever the molecular consequences of the R220W mutation, they cannot readily explain the clinical variability within this family. Transmission of FHH through the father is likely to be an important factor, as seen in other families.8,25 With paternal transmission, the maternal environment is one of normal calcium homeostasis. In utero, the fetal parathyroid gland and its partially inactivated CaSR senses the "normal" calcium level as low and stimulates fetal PTH release, thereby supporting increased fetal calcium at the expense of skeletal mineralization, which results in prenatal fractures and interferes with proper thoracic cage growth.23,26 A second factor may be mild vitamin D deficiency. Our patient had a low 25-hydroxyvitamin D level on day-of-life 2, consistent with longer-term maternal vitamin D insufficiency, which would be an additional stimulus on the parathyroid gland. Extreme prematurity in itself also may have affected this infant's skeletal mineralization. Bony mineralization is slower for premature infants, who lose the opportunity to acquire the large percentage of minerals usually transferred in the third trimester. It has also been postulated that the altered hormonal and biochemical environment of preterm postnatal existence contributes to decreased bone formation and increased reabsorption.27

Severe chronic lung disease (caused by prematurity, thoracic deformity, and ventilator dependency) and extra parathyroid tissue not identified during the initial surgery complicated our patient's course. Seven percent of the normal population has >4 parathyroid glands.28 In this case, our patient's hyperparathyroid state was prolonged for an additional 6 weeks until surgery could be repeated safely with a reasonable chance of success.

Total parathyroidectomy is the standard treatment for NSHPT2,29 and leads to significantly greater survival than subtotal parathyroidectomy or medical treatment.29 However, infants with milder NHPT and a heterozygous CaSR mutation may improve spontaneously, particularly if the only factor is an affected father but unaffected mother, when removal from the relatively hypocalcemic fetal environment allows the infant to obtain sufficient calcium to improve osteopenia.22,23

Pamidronate has been used in term neonates in the management of NSHPT2 to treat severe hypercalcemia until parathyroidectomy could be performed. In our case, pamidronate was introduced early with an aim to not only treat hypercalcemia but also increase bony density and improve chest wall mechanics and thereby limit development of severe chronic lung disease pending parathyroidectomy. In this case, to our knowledge the first extreme preterm infant treated with pamidronate, it was effective in reducing severe hypercalcemia and led to improvement in bone density on radiographs. We did not observe adverse effects in doses of 20 to 30 mg/m2 at intervals of 4 to 14 days in the short-term; unfortunately, it did not prevent development of thoracic deformity and ultimately fatal severe chronic lung disease.

CONCLUSIONS

NHPT remains a challenging disorder, particularly because the disease may be well advanced by delivery as a result of the unique interrelationship of the maternal-fetal dyad. Pamidronate showed some therapeutic benefit and did not have short-term adverse effects in this preterm infant, although use of this treatment could not overcome the impact of prematurity and development of chronic lung disease.

FOOTNOTES

Accepted May 4, 2007.

Address correspondence to Lisa Fox, MB, ChB, Neonatal Services, Royal Women's Hospital, 132 Grattan St, Carlton, Victoria 3053, Australia. E-mail: lisa.fox{at}rwh.org.au

The authors have indicated they have no financial relationships relevant to this article to disclose.

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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