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Year : 2022  |  Volume : 2  |  Issue : 2  |  Page : 117-120

Suspecting neonatal severe primary hyperparathyroidism in late onset neonatal sepsis

1 Department of Pediatrics, Government Medical College, Srinagar, Jammu and Kashmir, India
2 Department of Pediatric Nephrology, Government Medical College, Srinagar, Jammu and Kashmir, India

Date of Submission21-Jan-2022
Date of Decision15-Mar-2022
Date of Acceptance07-May-2022
Date of Web Publication30-May-2022

Correspondence Address:
Dr. Naseer Yousuf Mir
Department of Pediatrics, Government Medical College, Srinagar, Jammu and Kashmir
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_21_22

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Background: Neonatal severe primary hyperparathyroidism (NSPHPT) is disorder characterized by severe hypercalcemia and severe hyperparathyroidism resulting from a loss of function of the calcium-sensing receptor (CaSR), encoded by a gene located on the long arm of chromosome 3 (3q-13.3-21). It can be fatal if timely management is not initiated. Clinical Description: A 10-day-old exclusively breastfed girl presented with poor feeding, constipation, and lethargy for 2–3 days before admission. She was born of third-degree consanguinity to a primiparous woman with normal gestation. Born at term, with a birth weight of 3.1 kg, she was discharged uneventfully on day 3 of life. At admission, she was hemodynamically stable and normothermic but exhibited tachypnea, dehydrated with 15% weight loss as compared to birth weight, lethargy, and hypotonia. Salient investigations showed euglycemia, no dyselectrolytemia, and negative sepsis screen, but severe hypercalcemia and hyperparathyroidism. A final diagnosis of NSPHPT was made. Clinical exome sequencing showed homozygous CaSR gene frameshift mutation on chromosome 3. Management: Hypercalcemia was managed initially by standard protocol, including furosemide, hyperhydration, bisphosphonates, and cinacalcet. Subsequently, parathyroidectomy was performed at 2 months of age. Postoperatively, the infant is 5 months old and thriving well. Conclusion: NSPHPT should be considered in the presence of features of clinical sepsis, failure to timely regain birth weight, and a profile suggesting atypical calcium homeostasis.

Keywords: Calcium-sensing receptor mutation, hypercalcemia, hyperparathyroidism, parathyroidectomy

How to cite this article:
Mir NY, Andrabi S A, Ashraf M, Qureshi UA. Suspecting neonatal severe primary hyperparathyroidism in late onset neonatal sepsis. Indian Pediatr Case Rep 2022;2:117-20

How to cite this URL:
Mir NY, Andrabi S A, Ashraf M, Qureshi UA. Suspecting neonatal severe primary hyperparathyroidism in late onset neonatal sepsis. Indian Pediatr Case Rep [serial online] 2022 [cited 2023 Jun 3];2:117-20. Available from: http://www.ipcares.org/text.asp?2022/2/2/117/346251

Neonatal severe primary hyperparathyroidism (NSPHPT) is a rare autosomal recessive disorder of calcium homeostasis that manifests with severe hypercalcemia and metabolic bone disease in early neonatal life. The prevalence of this condition is reportedly two to five cases per 100,000 individuals.[1] The common manifestations include hypotonia, lethargy, polyuria, dehydration, gastrointestinal dysmotility, poor feeding, respiratory distress, and failure to thrive. NSPHPT can be fatal if left untreated.[2],[3]

This disorder results from a loss of function of the calcium-sensing receptor (CaSR), encoded by a gene located at 3q-13.3–21.[4] This G-protein-coupled receptor is found in many tissues in the body but predominantly in the parathyroid gland and kidneys, where its actions are more marked.[5] There are about 300 different CaSR inactivating mutations that have been discovered till date. The type of mutation affects the clinical severity and response to treatment. Homozygous inactivating CaSR mutations usually present with the aforementioned manifestations of severe hyperparathyroidism during the neonatal period. In contrast, heterozygous inactivating CaSR mutations are usually mild and asymptomatic, leading to familial hypocalciuric hypercalcemia (FHH).[6]

The cause of hypercalcemia in NSPHPT is multifactorial.[7] These include decreased sensitivity of receptors in the parathyroid glands to calcium levels, increased osteoclastic activity, and increased bone resorption leading to hypercalcemia. The goal of NSPHPT is to initially control the severe hypercalcemia by medical management (intravenous hyperhydration, diuretics, bisphosphonates, and calcimimetics), followed by definitive management (total or subtotal parathyroidectomy of the hyperplastic parathyroids).[8],[9],[10] We report a newborn admitted to our neonatal intensive care unit with a provisional diagnosis of late-onset sepsis with dehydration, who was subsequently diagnosed with NSHPT. The main aim is sharing the challenges that we faced in the management.

  Clinical Description Top

A10 days old baby girl presented with parental complaints of poor feeding, lethargy, constipation for 3 days, and decreased urine output for a day. The baby was born to a 27-year-old primiparous woman by cesarean section in a private hospital. The antenatal period was uneventful, with normal quickening, perception of fetal movements, and absence of any medical or obstetric illnesses. The mother was immunized and did not receive any medication during pregnancy except for routine iron, calcium, and folic acid supplementation. There was no history of maternal illness or any high-risk factors for neonatal sepsis preceding the birth. The baby cried immediately after birth, weighed 3.1 kg, and had no immediate postnatal complications. She was started on breastfeeding soon after delivery and discharged on day 3 of life. She was not given any prelacteals. The baby became symptomatic on day 7 of life with the aforementioned complaints. There was no history of fever, vomiting, cough, coryza, difficulty in breathing, excessive crying, seizures, abdominal distention, jaundice, or receiving any drugs or “ghutti.” She was first in birth order and the product of a third-degree consanguineous marriage. There was no significant family history of unexplained neonatal or infantile hospitalizations or death.

On examination, the baby was lethargic, moderately dehydrated, had a heart rate of 150/min, respiratory rate of 64/min (with no retractions), oxygen saturation of 95% on room air, blood pressure 66/42 mmHg, the temperature of 36.5°C, and capillary refilling time of 3 s. The weight at admission was 2.5 kg (indicating a weight loss of 600 g since birth), length was 51 cm (between 1 and 2 standard deviations [SD]), and head circumference was 35.5 cm (between 1 and 2 SD). The general physical examination revealed the absence of pallor, icterus, or gross congenital anomalies. The anterior fontanelle was normal in size and neither depressed nor bulging. Although she was hypotonic, she was moving all her limbs spontaneously and equally. There was no cranial nerve or focal neurological deficit. The abdominal examination did not detect any hepatosplenomegaly. The rest of the systemic examination was unremarkable. Based on this evaluation, we kept a possibility of late-onset sepsis and dehydration.

The blood sugar level was 96 mg/dl. The baby was immediately started on intravenous fluids (a bolus followed by maintenance fluids), first-line antibiotics (ampicillin and gentamicin), and oxygen support. Initial investigations sent included sepsis screen, blood sugar, liver function tests, kidney function tests (KFTs), C-reactive protein (CRP), and a blood culture. The sepsis screen was negative (CRP 3 mg/dl, normal total leukocyte count, and absolute neutrophil count). Hence, a lumbar puncture was not done. The blood culture was also later reported to be sterile. The liver function and KFTs were normal (serum sodium 138 mEq/ml, serum potassium 3.9 mEq/ml, serum creatinine 0.58 mg/dl, and serum urea 25 mg/dl). The ultrasound of the abdomen and cranium was also normal. These results excluded our first impression of late-onset sepsis. Salient biochemical abnormalities noted were increased serum calcium 35.5 (normal 8.5–10.5 mg/dl), low phosphorus 2.1 (normal 3.5–7.5 mg/dl), and high alkaline phosphatase 860 IU/L (normal 100–800). This profile prompted us to plan parathyroid hormone (PTH) and Vitamin D levels. PTH was markedly raised to 660 pg/ml (normal 6.5–36.5 pg/ml). The results of the investigations are given in [Table 1]. Thus, the differentials were narrowed down to disorders of the parathyroid gland, especially since the common causes of hypercalcemia (iatrogenic, acute renal failure, maternal Vitamin D intoxication, and hypoparathyroidism) were ruled out. Other differentials that were considered and disregarded are given in [Table 2]. Normal serum and urinary calcium and PTH levels in both parents ruled out FHH. The presence of severe persistent hypercalcemia and hyperparathyroidism, in a setting of a third-degree consanguineous marriage led us to suspect genetic causes of hypercalcemia. Therefore, we planned a clinical exome sequencing, which identified a homozygous CaSR gene frameshift mutation on chromosome 3, at 122003135delC;p.Tyr789fs location suggestive of NSPHPT. The final diagnosis was NSPHPT. Genetic counseling regarding the same was done.
Table 1: Salient investigations related to calcium homeostasis at admission

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Table 2: Differential diagnosis of neonatal severe primary hyperparathyroidism

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  Management and Outcome Top

After initially giving three boluses of 10 ml/kg/h for the dehydration, the baby was continued on intravenous fluid infusion along with injection of furosemide (1 mg/kg/dose). Despite this, hypercalcemia persisted. Hence, injection pamidronate was administered as a daily infusion (0.5 mg/kg over 4 h) for 3 days. Since this also did not decrease the calcium levels either, it was discontinued; injection of cinacalcet (0.5 mg/kg/day) was started on the 4th day of admission. Following this, the calcium level decreased to 12.5 mg/dl within 48 h. Over the next 2 days, it had further decreased to 11.1 mg/dl. The baby was switched to oral cinacalcet from day 6th onward. Intravenous furosemide was continued till 1 day before discharge. At discharge, 18th day of life and 9th day of admission, the baby was on exclusive breastfeeds, hemodynamically stable, displayed adequate weight gain, and was clinically active and normocalcemic on oral cinacalcet (30 mg/day). However, on her first follow-up visit (27th day of life), we detected hypercalcemia (despite good compliance with the medication) with a level of 15 mg/dl, although the ultrasound abdomen did not find calcium deposits. A pediatric surgery consultation was taken following, and the parents were counseled about the need and urgency of total parathyroidectomy. There was an inadvertent delay due to the ongoing COVID-19 pandemic. During the period of first admission to surgery the baby had two episodes of hypercalcemia. For the same reason she was admitted at 30th and 45th days of life respectively. The baby was operated at 2 months of age, and the postoperative period was uneventful. The histopathological biopsy report showed parathyroid hyperplasia with no features of malignancy. The baby is currently on regular follow-up, receiving daily replacement therapy of calcium 500 mg, Vitamin D 1000 IU, and calcitriol 0.25 μg. At 5 months of age, she is thriving well, with a weight of 6.4 kg and a length of 68 cm.

  Discussion Top

NSPHT is a rare condition and is not often included in the differential diagnoses of a sick and dehydrated neonate and thus often gets missed. This condition should be considered in the neonatal period if manifestations such as lethargy, polyuria, failure to thrive, dehydration, gastrointestinal dysmotility, or poor feeding are present; or if hypercalcemia is identified. This is what happened in this case. After sepsis was excluded, laboratory reports related to calcium homeostasis became available; treatment for severe hypercalcemia was initiated as per the standard protocol. The biochemical phenotype of severe hypercalcemia and hyperparathyroidism leads us to suspect two differentials; an underlying genetic disorder (which was eventually established) and neoplasia such as adenomas of the parathyroid gland (which was excluded by histopathology).

Bisphosphonates such as zoledronic acid are being increasingly used in neonates and children with hypercalcemia to inhibit the osteoclastic bone resorption that gets triggered by the uncontrolled hyperparathyroidism in NSPHPT.[11] Another drug that is frequently used is cinacalcet. This is a type II calcimimetic that behaves as a positive allosteric activator of the CaSR.[2] It interacts with the transmembrane domain and makes the receptor more sensitive to Ca2+. These events suppress PTH, thereby increasing renal calcium excretion and effectively decreasing the serum calcium levels. Ideally, total parathyroidectomy should be done as soon as the condition has been detected, and the acute crisis managed, as outlined earlier. Total parathyroidectomy with or without autotransplantation of a part of the parathyroid gland is the definitive therapy. The child will need lifelong calcium and supplementation due to the iatrogenic state of surgical hypoparathyroidism and subsequent hypocalcemia.

As NSPHPT is an extremely rare condition, missing the diagnosis can be life-threatening for a neonate. Early diagnosis and prompt and appropriate medical management are very important in the initial phase for stabilization and prevention of complications. Given that there is a wide repertoire of manifestations due to mutations in CaSR, clinicians must keep a high index of suspicion in a newborn with hypercalcemia, irrespective of symptoms, and investigate accordingly once concurrent hyperparathyroidism is identified.

Authors contributions

NYM and SANA were involved in patient management and drafted the case report; MA conceived the concept and critically analyzed the manuscript, and UAQ was overall supervising the case management.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Mallet E. Primary hyperparathyroidism in neonates and childhood. Hom Res Pediatr 2008;69:180-8.  Back to cited text no. 1
Gannon AW, Monk HM, Levine MA. Cinacalcet monotherapy in neonatal severe hyperparathyroidism: A case study and review. J Clin Endocrinol Metab 2014;99:7-11.  Back to cited text no. 2
Ward DT. Calcium receptor-mediated intracellular signalling. Cell Calcium 2004;35:217-28.  Back to cited text no. 3
Hendy GN, D'Souza-Li L, Yang B, et al. Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat 2000;16:281-96.  Back to cited text no. 4
Lu JY, Yang Y, Gnacadja G, et al. Effect of the calcimimeticR-568 [3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl) ethyl)-1-propanamine] on correcting inactivating mutations in the human calcium-sensing receptor. J Pharmacol Exp Ther 2009;331:775-86.  Back to cited text no. 5
Reh CM, Hendy GN, Cole DE, et al. Neonatal hyperparathyroidism with a heterozygous calcium-sensing receptor (CASR) R185Q mutation: Clinical benefit from cinacalcet. J Clin Endocrinol Metab 2011;96:E707-12.  Back to cited text no. 6
Wilhelm-Bals A, Parvex P, Magdelaine C, et al. Successful use of bisphosphonate and calcimimetic in neonatal severe primary hyperparathyroidism. Pediatrics 2012;129:e812-6.  Back to cited text no. 7
García-García E, Domínguez-Pascual I, Requena-Díaz M, et al. Intraoperative parathyroid hormone monitoring in neonatal severe primary hyperparathyroidism. Pediatrics 2014;134:e1203-5.  Back to cited text no. 8
Savas-Erdeve S, Sagsak E, Keskin M, et al. Treatment experience and long-term follow-up data in two severe neonatal hyperparathyroidism cases. J Pediatr Endocrinol Metab2016;29:1103-10.  Back to cited text no. 9
Waller S, Kurzawinski T, Spitz L, et al. Neonatal severe hyperparathyroidism: Genotype/phenotype correlation and the use of pamidronate as rescue therapy. Eur J Pediatr 2004;163:589-94.  Back to cited text no. 10
García Soblechero E, Ferrer Castillo MT, Jiménez Crespo B, et al. Neonatal hypercalcemia due to a homozygous mutation in the calcium-sensing receptor: Failure of cinacalcet. Neonatology 2013;104:104-8.  Back to cited text no. 11


  [Table 1], [Table 2]


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