Neonatal severe primary hyperparathyroidism (NSHPT) is a rare endocrine disorder characterized by striking hyperparathyroidism, marked hypercalcemia, and metabolic bone disease. First symptoms manifest shortly after birth and require urgent medical attention to lower serum calcium levels and prevent neurological complications. Both calcimimetic therapy and surgical parathyroidectomy enable a long-term resolution of NSHPT, which may be fatal if left untreated.
In the literature, NSHPT is sometimes simply referred to as neonatal severe hyperparathyroidism or neonatal hyperparathyroidism.
NSHPT usually presents shortly after birth with life-threatening primary hyperparathyroidism and severe hypercalcemia . Affected children appear lethargic, suffer from hypotonia, respiratory distress, and dysphagia. Feeding difficulties are common, as are polyuria and dehydration . Critical illness in infancy, however, is not an exclusion criterion for NSHPT or may be overcome with symptomatic treatment. These patients represent at several weeks or even months of age with failure to thrive and complex developmental delays. Motor disturbances are most frequently reported, although hypercalcemia-related neurological decompensation eventually affects all types of skills.
NSHPT should also be considered in the differential diagnosis for neonates with signs and symptoms of metabolic bone disease. A bell-shaped chest, metaphyseal irregularities, diffuse osteopenia, and periosteal reactions may be observed in affected individuals .
Entire Body System
- Poor Feeding
All children had features of severe bone demineralisation and a combination of vomiting, dehydration, poor feeding, and failure to thrive. One child had multiorgan failure, rib fractures with flail chest necessitating ventilation on ITU. [endocrine-abstracts.org]
Case Report An 8-day-old boy was referred to our hospital for poor feeding and hypotonia from the second day of his life. He was a full-term baby, born with appropriate Apgar score. [theijcp.org]
He was admitted to another hospital at 18 days of age with severe global hypotonia, poor feeding, failure to thrive, signs of dehydration, and lethargy. [pediatrics.aappublications.org]
Case Report A 4-week, female infant was admitted to our hospital with poor feeding and lethargy for 2 days and seizures for 4 h. She was born at 39 weeks, uneventfully, to third-degree consanguineous parents with birth weight of 3.4 Kg. [thetrp.net]
- Absent Deep Tendon Reflexes
Clinical findings On physical examination, lethargy, hypotonia and absent deep tendon reflexes were evident and a weight loss of 465 g since birth was recorded.. Blood pressure was 68/40 mmHg and SaO2 = 97% on room air. [bmcpediatr.biomedcentral.com]
- Motor Disturbances
Motor disturbances are most frequently reported, although hypercalcemia-related neurological decompensation eventually affects all types of skills. [symptoma.com]
Laboratory analyses of blood samples are the basis of NSHPT diagnosis. Hypercalcemia, hypophosphatemia, increased levels of alkaline phosphatase and parathyroid hormone. Serum 25-hydroxyvitamin D levels may be reduced   , and urine analysis may reveal hypocalciuria. If not already done, parents should now be asked about any family of hypercalcemia, renal function impairment, or metabolic bone disease .
Diagnostic imaging is helpful to relate biochemical abnormalities to skeletal malformations, although they don't necessarily correlate in their extent. Radiographs may reveal a generalized undermineralization of the bone with rib cage deformities and metaphyseal widening of the long bones. Subperiosteal erosions may be noted and patients are prone to fractures .
If demographic data, laboratory results, and imaging findings all support the tentative diagnosis of NSHPT, then genetic studies should be carried out for confirmation. What's more, the identification of the underlying mutation is crucial for the familial workup and prenatal diagnosis. Except in cases of de novo CASR mutations, the parents of an NSHPT must be carriers of these gene defects and should be examined for familial hypocalciuric hypercalcemia .
In the workup of NSHPT, the patient's renal function should be controlled. Nephrolithiasis and nephrocalcinosis are common complications of primary hyperparathyroidism and have been described in children with NSHPT .
The gold standard of treatment has long since been surgical parathyroidectomy, and some authors continue to argue that total parathyroidectomy is generally required and to be performed urgently in order to prevent a fatal outcome . Notwithstanding, several case reports have been published that demonstrate the feasibility of successful medical management . Beyond that, serum calcium levels must be reduced immediately, and patients should be provided intravenous fluid hydration in combination with loop diuretic therapy. Bisphosphonates like pamidronate may also be administered but must be used carefully. Calcium and vitamin D intake must be restricted .
A total of five NSHPT patients have successfully been treated with cinacalcet monotherapy. This calcimimetic agent increases the sensitivity of the calcium-sensing receptor whose function is limited as a consequence of CASR mutations. Its response to high levels of extracellular calcium is improved and the secretion of parathyroid hormone is subsequently diminished . There are no general recommendations regarding the dosage of cinacalcet, and those five patients mentioned before received between 0.4 and 9.6 mg per kg and day    . In any case, electrolyte and parathyroid hormone levels should be monitored continuously to be able to adjust the dose to the needs of the individual patient.
It shall be mentioned that four of the five children were heterozygous for pathogenic CASR mutations and disposed of one functional wild-type allele. Two other patients who were shown to be homozygous for truncating CASR mutations failed to respond to cinacalcet therapy  , suggesting that parathyroidectomy may not be avoided in all cases. The patients' parathyroid glands are enlarged, appear hyperplastic and hypercellular, and parathyroidectomy may be performed with or without autotransplantation . Postoperatively, the intense remineralization of "hungry bones" may cause hypocalcemia, hypophosphatemia, and hypomagnesemia, and indicates symptomatic treatment. Hypocalcemia, however, may persist, and patients may require long-term calcium and calcitriol supplementation .
Of note, a transient form of NSHPT can be developed by heterozygous carriers of CASR mutations when the in utero development occurs in a normocalcemic maternal environment . Transient NSHPT is not an indication for surgery but for conservative management.
The aim of NSHPT treatment is the (near) normalization of electrolyte levels and parathyroid hormone secretion, so as to facilitate physiological development. Mild hypercalcemia may persist, but most patients catch up on their developmental delays. In severe cases, though, permanent sequelae may result from irreversible damage of the nervous system and cerebral atrophy . Metabolic bone disease is generally overcome. Body weight and height increase upon the regulation of bone metabolism, although patients may remain below average values .
Cinacalcet may be required throughout life, although no studies have yet been published regarding the possible consequences of tapering off the calcimimetic after prolonged therapy. Similarly, postoperative complications of parathyroidectomy, namely chronic hypoparathyroidism, may imply the need for lifelong medication to maintain calcium homeostasis.
If left untreated, NSHPT may result in severe neurological impairment, loss of consciousness, and death within three months after birth  . Long-term survival in the absence of parathyroidectomy and treatment with calcimimetics has been reported in isolated cases, though. The respective patients showed minor cognitive deficits, but a causal relationship has not been demonstrated  .
NSHPT is caused by loss-of-function mutations of the CASR gene, which is located at 3q13.33-q21.1 and encodes for parathyroid-cell calcium-sensing receptor 1. More than 250 CASR mutations have been reported to date, with most of them being inactivating mutations .
Both autosomal dominant and autosomal recessive patterns of inheritance have been described, and while most patients are homozygous or compound heterozygous for pathogenic CASR mutations, heterozygosity may also result in NSHPT: CASR mutation R185Q has been shown to exert a dominant-negative effect on the wild-type receptor . Otherwise, heterozygosity for inactivating CASR mutations is usually related to familial hypocalciuric hypercalcemia, a rather mild form of hypercalcemia .
Primary hyperparathyroidism is a rather common endocrine disorder whose annual incidence has been estimated at 2 in 10,000 inhabitants. Large shares of patients are assumed to be asymptomatic, so the true incidence of the disease may be even higher . Yet, familial forms of primary hyperparathyroidism account for no more than 2-5% of the total number of cases, and NSHPT is only one of several hereditary disorders that may give rise to primary hyperparathyroidism  . Less than 100 cases have been described so far, and according to the available literature, both boys and girls are affected equally . According to current knowledge, there are no differences by race or ethnicity either.
Parathyroid-cell calcium-sensing receptor 1 is a G protein-coupled receptor that localizes to the plasma membrane and plays an essential role in the maintenance of calcium homeostasis. CASR expression is highest in the parathyroid glands, calcitonin-secreting C-cells of the thyroid gland, and kidney, all of which respond to changes in the concentration of circulating calcium . Upon such changes, intracellular signaling cascades are modulated that relate to the secretion of parathyroid hormone and the renal excretion of cations. Under physiological conditions, high levels of extracellular calcium trigger the activation of the receptor, the reduction of parathyroid hormone release, and the increase of renal calcium excretion.
In the case of NSHPT, the set point of parathyroid cells, i.e., the extracellular calcium concentration at which the secretion of parathyroid hormone is half-maximally inhibited, is much increased. Patients become hypercalcemic but are unable to counteract hypercalcemia by stimulating the renal excretion of calcium. Calcium may not even be detectable in urine samples obtained from these individuals . Gain-of-function mutations of CASR, however, have the opposite effect. The set point is lowered, and patients may develop autosomal dominant hypocalcemia, with or without Bartter syndrome .
Families known to harbor pathogenic CASR mutations should be referred for genetic counseling. NSHPT is a treatable disease but may have devastating consequences if not recognized and adequately treated. The prenatal identification of CASR mutations is feasible, as is the early postnatal determination of serum calcium levels, and the respective offers should be taken up if there is a family history of familial hypocalciuric hypercalcemia or NSHPT.
With regard to autosomal recessive forms of NSHPT, the general public should be informed about the risks of consanguineous marriage and reproduction  .
NSHPT is a rare endocrine disorder caused by functional deficiencies of the calcium-sensing receptor expressed by parathyroid cells and other tissues in the human body. The respective receptor is encoded for by the CASR gene, and several hundred loss and gain-of-function mutations have been described to date. Loss-of-function mutations are related to a decreased sensitivity for calcium, resulting in hypercalcemia and primary hyperparathyroidism. As a general rule, heterozygosity for inactivating CASR mutations leads to asymptomatic familial hypocalciuric hypercalcemia, and homozygosity and compound heterozygosity provoke NSHPT . Notwithstanding, severe disease has been reported in heterozygous patients, too .
Parathyroidectomy has long since been the standard of NSHPT treatment. More recently, however, cinacalcet therapy has gained considerable attention as a possible alternative to surgery . The type of mutation has been suggested to influence a patient's response to treatment, and distinct authors have proposed the creation of a database associating genotypes, phenotypes, and responses to therapy. As of today, there are no guidelines that help with the decision for or against the medical or surgical management of the disease, and there's no preferred order of therapeutic approaches  . In any case, the timely diagnosis of NSHPT is among the most important prognostic factors, and lack of awareness contributes to diagnostic delays. Every effort should thus be made to raise the awareness for this rare but potentially fatal disease.
The parathyroid glands are small endocrine glands in the anterior neck region. They produce a hormone that raises the serum calcium level; it is called parathyroid hormone and stimulates the mobilization of calcium from the bones and inhibits the renal excretion of this mineral. The secretion of parathyroid hormone is tightly regulated and responds to the actual concentration of circulating calcium. If there is excess calcium in the blood, less parathyroid hormone is released so the calcium level can decrease.
In patients with primary hyperparathyroidism, parathyroid cells are unable to sense increased calcium levels. Thus, no measures are taken to decrease those levels, to stop bone demineralization, and to augment the urinary excretion of calcium. Such conditions may be caused by gene defects, as is the case with neonatal severe primary hyperparathyroidism (NSHPT). Patients with NSHPT carry mutations of the CASR gene, which encodes for parathyroid-cell calcium-sensing receptor 1. They develop hypercalcemia, hypotonia, respiratory distress, and dysphagia, usually within days after birth. If left untreated, failure to thrive and developmental delays may manifest, or severe neurological impairment, loss of consciousness, and death.
In order to prevent those complications, NSHPT should be diagnosed and treated as early as possible. The diagnosis is based on the child's family history, laboratory analyses of blood samples, X-ray examinations, and genetic studies. There are two approaches to treatment, namely the pharmacological modulation of parathyroid calcium sensing and the surgical removal of the parathyroid glands. Both aim at the restoration of calcium homeostasis and the normalization of development and bone metabolism.
NSHPT is a hereditary disease, and most patients inherit defective CASR alleles from both of their parents. This implies that there is an increased risk for siblings to be born with the same disease, which should prompt genetic counseling and prenatal diagnosis. Furthermore, the parents themselves may have hypercalcemia, even in the absence of symptoms, and should be examined accordingly.
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