RARE DISEASE
Neonatal severe primary hyperparathyroidism
Neonatal severe primary hyperparathyroidism
Neonatal severe primary hyperparathyroidism
Synonyms: NSHPT
Synonyms: NSHPT
Synonyms: NSHPT
Drug discovery
2
drugs
With orphan designations
Overview
Neonatal severe primary hyperparathyroidism (NSHPT) is a rare, life-threatening autosomal recessive disorder caused by homozygous or heterozygous inactivating mutations in the CASR gene, impairing calcium-sensing receptor function [6][11]. It manifests with severe hypercalcemia (>3.5 mM), metabolic bone disease, respiratory distress, hypotonia, and fractures within days to months of birth [1][6][12]. Early intervention involves aggressive medical management (hydration, bisphosphonates, calcimimetics), but definitive treatment often requires total parathyroidectomy, necessitating lifelong calcium/vitamin D supplementation [8][13][17].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases
Research Papers
111 drug discovery papers about Neonatal severe primary hyperparathyroidism, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
111 drug discovery papers about Neonatal severe primary hyperparathyroidism, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2024-10-24 | Generation of CRISPR/Cas9 modified human iPSC line with correction of heterozygous mutation in exon 6 of the CaSR gene.
The calcium-sensing receptor (CaSR) gene encodes a cell membrane G protein-coupled receptor (GPCR) which has a key role in maintaining the extracellular Ca2+ homeostasis. We aimed at correcting the compound heterozygous mutation in the 6th [c.1656delA, p.I554SfsX73] and 7th [c.2217 T > A, p.C739X] exons of the CASR gene which the original patient-derived iPSC line had. The mutation is associated with neonatal severe primary hyperparathyroidism of the patient. We generated and characterized a CRISP/Cas9-edited hiPSC line with the restored sequence in the sixth exon of the CASR gene, bearing only heterozygous mutation in the 7th exon. The results showed that the new genetically modified cell line has karyotype without abnormalities, typical hiPSCs morphology, characteristic expression of pluripotency markers, and ability to develop into three germ layers, and differentiates in chondrogenic, adipogenic, osteogenic directions. This new cell line will complement the existing pool of CaSR-mutated cell lines, a valuable resource for in-depth understanding of neonatal severe primary hyperparathyroidism. This will allow further exploration of the application of pharmacological drugs in the context of personalized medicine to correct Ca-homeostasis disorders.
2000-08-01 | Cell transplantation for endocrine disorders
Current hormonal replacement therapy for endocrine disorders cannot, unfortunately, reproduce the complex metabolic interactions of hormones. The organ or cell transplantation would be a more physiological approach to the treatment of endocrine disorders. For decades, remarkable progress in organ or cell transplantation in endocrine disorders has been made, especially in recent years. But there are many limitations in the widespread application of allotransplantation because of rejection. Various methods of immunomanipulations designed to overcome rejection have been proposed, which include immunosuppression, immunomodulation and immunoisolation. The transplantation of immunoisolated cells and some clinical results of the transplants were reviewed. Also a perspective for future directions on endocrine cell transplantation was provided in this review. Human islet cell transplantation for the cure of diabetes was emphasized in this chapter and other cell transplantation for endocrine disorders was also discussed briefly, including parathyroid tissue transplantation, bioartificial thyroid transplantation and adrenal cell transplantation.
small molecules
2026-05-19 | Nine-year cinacalcet monotherapy in a child with neonatal severe hyperparathyroidism caused by compound heterozygous CASR mutations.
Neonatal severe primary hyperparathyroidism (NSHPT) is a rare, potentially life-threatening disorder caused by loss-of-function mutations in the CASR gene. Treatment traditionally includes hydration, diuretics, bisphosphonates, and parathyroidectomy. Long-term data on pharmacological therapy with cinacalcet are limited. We report a female infant with NSHPT due to compound heterozygous CASR variants (c.893C>T, p.Ala298Val; c.2414A>C, p.Lys805Thr). Initial therapy with bisphosphonates provided transient calcium reduction. Cinacalcet monotherapy was started in the third week of life, with empirically guided dose titration. Follow-up over nine years showed stable mild hypercalcemia (approximately 3 mmol/L), normal or slightly elevated PTH, normal growth and cognitive development, absence of nephrocalcinosis, and preserved bone mineral density. This case suggests that long-term cinacalcet therapy may provide sustained biochemical control in selected patients with NSHPT carrying CASR variants with residual receptor function. Long-term cinacalcet monotherapy may provide sustained biochemical control and normal development in selected patients with NSHPT carrying CASR variants with residual receptor function.
2025-03-28 | Neonatal Severe Hyperparathyroidism: Anaesthetic Considerations for Removal of Pea-size Glands in Children.
Neonatal severe hyperparathyroidism (NSHPT) is an extremely rare disorder with uncontrolled severe hypercalcemia and its clinical manifestations. It is caused by a mutation in the calcium-sensing receptor (CaSR) gene, which modulates the negative feedback of parathormone. We present anaesthetic management of two children with NSHPT who were posted for total parathyroidectomy as a life saving procedure. Both patients presented with lethargy, failure to thrive, and hypotonia. Intraoperative anaesthetic challenges include susceptibility to bradycardia, prolonged QT interval, precipitation of hypercalcemic crisis in the form of renal failure, hyperkalemia and electrocardiography changes, unpredictable response to neuromuscular blockade, susceptibility to recurrent laryngeal nerve injury, refractory hypocalcemia, which may start developing within six hours after surgery. Anaesthetic goals include preoperative optimisation of serum calcium with subcutaneous. Calcitonin, intravenous pamidronate and tablet cinacalcet, which are calcimimetics, maintenance of hydration and readiness to deal with intraoperative hypercalcemic crises. Anaesthetic management of NSHPT posted for total parathyroidectomy is challenging. To the best of our knowledge, there is no anaesthetic literature published to this day and only four surgical cases have been reported. Genome sequencing in both patients showed a CaSR gene mutation that is homozygous for a suspected pathogenic variant. Management requires a preoperative multidisciplinary approach for severe hypercalcemia and postoperative refractory hypocalcemia. These patients need lifelong calcium and vitamin D supplementation.
2025-03-20 | Neonatal Severe Primary Hyperparathyroidism: A Case Report on the Successful Management of Hypercalcemia with Phosphorus Supplementation
Neonatal Severe Primary Hyperparathyroidism (NSHPT) is a rare autosomal recessive disorder caused by inactivating mutations in the calcium-sensing receptor (CaSR) gene, leading to severe hypercalcemia and elevated parathyroid hormone levels. We report the case of a 7-day-old girl who presented with hypercalcemic crisis and was treated with hyperhydration, bisphosphonates, and phosphorus supplementation. Despite initial management, cinacalcet showed limited efficacy, suggesting a homozygous phenotype. Long-term management remains challenging, with surgery being the ultimate solution. Genetic analysis is crucial to guide treatment strategies.
2025-01-22 | Neonatal severe hyperparathyroidism with inactivating calcium sensing receptor (CaSR) mutation (p.I81K).
Neonatal severe hyperparathyroidism (NSHPT) is a rare condition characterized by inactivating mutations in the calcium-sensing receptor (CaSR) gene, leading to significant hypercalcemia and related complications. We present a case of a six-day-old male infant with weakness, jaundice, and hypotonia, later diagnosed with NSHPT due to a known homozygous CaSR mutation (c.242T>A; p.I81K). Initial laboratory findings revealed markedly elevated serum calcium levels and high parathyroid hormone levels which were compatible with primary hyperparathyroidism. After initial management, bisphosphonates were administered, resulting in the patient remaining normocalcemic for 11 months, although hyperparathyroidism persisted. Then, due to the ongoing hyperparathyroidism, cinacalcet was added and continued for nine months. Finally, a total parathyroidectomy was performed. Postoperatively, the patient developed hypoparathyroidism, necessitating long-term supplementation with calcium and calcitriol. By the last follow-up at 3 years, the patient exhibited normal growth parameters and no neurodevelopmental deficits. This case underscores the importance of early diagnosis and intervention in NSHPT and highlights the critical role of medical treatment, surgical management and long-term follow-up in optimising patient outcomes. Continued research is essential to enhance understanding and treatment strategies for NSHPT.
2022-12-16 | Brown Adipose Tissue Biodistribution and Correlations Particularities in Parathyroid Pathology Personalized Diagnosis
Brown adipose tissue (BAT) participates in the regulation of whole-body metabolism by producing a variety of adipokines. This study investigates into the BAT pattern and the clinical aspects of overweight and obese (OOB) vs. non-obese (NO) hyperparathyroidism (HPT) patients with the aim of assessing the impact of BAT and obesity on HPT. Parathyroid scans performed on 441 HPT patients between 2015 and 2020 were retrospectively analyzed in order to select the images with active BAT. Based on their BMI, the patients with active BAT were divided into OOB vs. NO. The results showed that BAT was present in cervical and supraclavicular regions, with a single localization especially among NO vs. multiple sites among OOB. The (total counts/pixels)BAT/(total counts/pixels)non-BAT ratio in the right cervical localization showed a significant difference between the groups with higher values in OOB. BMI, PTH, FT4, vitamin D, magnesium, creatinine, and urea had significant correlations with BAT ratios. The predictive values showed that right cervical ratios higher than 1.52 and right supraclavicular ratios lower than 1.15 indicated an increased probability of being OOB. The significant correlations between BAT activation in OOB vs. NO and HPT clinical parameters could be useful for developing potential treatments based on this tissue.
cell therapies
2024-10-24 | Generation of CRISPR/Cas9 modified human iPSC line with correction of heterozygous mutation in exon 6 of the CaSR gene.
The calcium-sensing receptor (CaSR) gene encodes a cell membrane G protein-coupled receptor (GPCR) which has a key role in maintaining the extracellular Ca2+ homeostasis. We aimed at correcting the compound heterozygous mutation in the 6th [c.1656delA, p.I554SfsX73] and 7th [c.2217 T > A, p.C739X] exons of the CASR gene which the original patient-derived iPSC line had. The mutation is associated with neonatal severe primary hyperparathyroidism of the patient. We generated and characterized a CRISP/Cas9-edited hiPSC line with the restored sequence in the sixth exon of the CASR gene, bearing only heterozygous mutation in the 7th exon. The results showed that the new genetically modified cell line has karyotype without abnormalities, typical hiPSCs morphology, characteristic expression of pluripotency markers, and ability to develop into three germ layers, and differentiates in chondrogenic, adipogenic, osteogenic directions. This new cell line will complement the existing pool of CaSR-mutated cell lines, a valuable resource for in-depth understanding of neonatal severe primary hyperparathyroidism. This will allow further exploration of the application of pharmacological drugs in the context of personalized medicine to correct Ca-homeostasis disorders.
2000-08-01 | Cell transplantation for endocrine disorders
Current hormonal replacement therapy for endocrine disorders cannot, unfortunately, reproduce the complex metabolic interactions of hormones. The organ or cell transplantation would be a more physiological approach to the treatment of endocrine disorders. For decades, remarkable progress in organ or cell transplantation in endocrine disorders has been made, especially in recent years. But there are many limitations in the widespread application of allotransplantation because of rejection. Various methods of immunomanipulations designed to overcome rejection have been proposed, which include immunosuppression, immunomodulation and immunoisolation. The transplantation of immunoisolated cells and some clinical results of the transplants were reviewed. Also a perspective for future directions on endocrine cell transplantation was provided in this review. Human islet cell transplantation for the cure of diabetes was emphasized in this chapter and other cell transplantation for endocrine disorders was also discussed briefly, including parathyroid tissue transplantation, bioartificial thyroid transplantation and adrenal cell transplantation.
small molecules
2026-05-19 | Nine-year cinacalcet monotherapy in a child with neonatal severe hyperparathyroidism caused by compound heterozygous CASR mutations.
Neonatal severe primary hyperparathyroidism (NSHPT) is a rare, potentially life-threatening disorder caused by loss-of-function mutations in the CASR gene. Treatment traditionally includes hydration, diuretics, bisphosphonates, and parathyroidectomy. Long-term data on pharmacological therapy with cinacalcet are limited. We report a female infant with NSHPT due to compound heterozygous CASR variants (c.893C>T, p.Ala298Val; c.2414A>C, p.Lys805Thr). Initial therapy with bisphosphonates provided transient calcium reduction. Cinacalcet monotherapy was started in the third week of life, with empirically guided dose titration. Follow-up over nine years showed stable mild hypercalcemia (approximately 3 mmol/L), normal or slightly elevated PTH, normal growth and cognitive development, absence of nephrocalcinosis, and preserved bone mineral density. This case suggests that long-term cinacalcet therapy may provide sustained biochemical control in selected patients with NSHPT carrying CASR variants with residual receptor function. Long-term cinacalcet monotherapy may provide sustained biochemical control and normal development in selected patients with NSHPT carrying CASR variants with residual receptor function.
2025-03-28 | Neonatal Severe Hyperparathyroidism: Anaesthetic Considerations for Removal of Pea-size Glands in Children.
Neonatal severe hyperparathyroidism (NSHPT) is an extremely rare disorder with uncontrolled severe hypercalcemia and its clinical manifestations. It is caused by a mutation in the calcium-sensing receptor (CaSR) gene, which modulates the negative feedback of parathormone. We present anaesthetic management of two children with NSHPT who were posted for total parathyroidectomy as a life saving procedure. Both patients presented with lethargy, failure to thrive, and hypotonia. Intraoperative anaesthetic challenges include susceptibility to bradycardia, prolonged QT interval, precipitation of hypercalcemic crisis in the form of renal failure, hyperkalemia and electrocardiography changes, unpredictable response to neuromuscular blockade, susceptibility to recurrent laryngeal nerve injury, refractory hypocalcemia, which may start developing within six hours after surgery. Anaesthetic goals include preoperative optimisation of serum calcium with subcutaneous. Calcitonin, intravenous pamidronate and tablet cinacalcet, which are calcimimetics, maintenance of hydration and readiness to deal with intraoperative hypercalcemic crises. Anaesthetic management of NSHPT posted for total parathyroidectomy is challenging. To the best of our knowledge, there is no anaesthetic literature published to this day and only four surgical cases have been reported. Genome sequencing in both patients showed a CaSR gene mutation that is homozygous for a suspected pathogenic variant. Management requires a preoperative multidisciplinary approach for severe hypercalcemia and postoperative refractory hypocalcemia. These patients need lifelong calcium and vitamin D supplementation.
2025-03-20 | Neonatal Severe Primary Hyperparathyroidism: A Case Report on the Successful Management of Hypercalcemia with Phosphorus Supplementation
Neonatal Severe Primary Hyperparathyroidism (NSHPT) is a rare autosomal recessive disorder caused by inactivating mutations in the calcium-sensing receptor (CaSR) gene, leading to severe hypercalcemia and elevated parathyroid hormone levels. We report the case of a 7-day-old girl who presented with hypercalcemic crisis and was treated with hyperhydration, bisphosphonates, and phosphorus supplementation. Despite initial management, cinacalcet showed limited efficacy, suggesting a homozygous phenotype. Long-term management remains challenging, with surgery being the ultimate solution. Genetic analysis is crucial to guide treatment strategies.
2025-01-22 | Neonatal severe hyperparathyroidism with inactivating calcium sensing receptor (CaSR) mutation (p.I81K).
Neonatal severe hyperparathyroidism (NSHPT) is a rare condition characterized by inactivating mutations in the calcium-sensing receptor (CaSR) gene, leading to significant hypercalcemia and related complications. We present a case of a six-day-old male infant with weakness, jaundice, and hypotonia, later diagnosed with NSHPT due to a known homozygous CaSR mutation (c.242T>A; p.I81K). Initial laboratory findings revealed markedly elevated serum calcium levels and high parathyroid hormone levels which were compatible with primary hyperparathyroidism. After initial management, bisphosphonates were administered, resulting in the patient remaining normocalcemic for 11 months, although hyperparathyroidism persisted. Then, due to the ongoing hyperparathyroidism, cinacalcet was added and continued for nine months. Finally, a total parathyroidectomy was performed. Postoperatively, the patient developed hypoparathyroidism, necessitating long-term supplementation with calcium and calcitriol. By the last follow-up at 3 years, the patient exhibited normal growth parameters and no neurodevelopmental deficits. This case underscores the importance of early diagnosis and intervention in NSHPT and highlights the critical role of medical treatment, surgical management and long-term follow-up in optimising patient outcomes. Continued research is essential to enhance understanding and treatment strategies for NSHPT.
2022-12-16 | Brown Adipose Tissue Biodistribution and Correlations Particularities in Parathyroid Pathology Personalized Diagnosis
Brown adipose tissue (BAT) participates in the regulation of whole-body metabolism by producing a variety of adipokines. This study investigates into the BAT pattern and the clinical aspects of overweight and obese (OOB) vs. non-obese (NO) hyperparathyroidism (HPT) patients with the aim of assessing the impact of BAT and obesity on HPT. Parathyroid scans performed on 441 HPT patients between 2015 and 2020 were retrospectively analyzed in order to select the images with active BAT. Based on their BMI, the patients with active BAT were divided into OOB vs. NO. The results showed that BAT was present in cervical and supraclavicular regions, with a single localization especially among NO vs. multiple sites among OOB. The (total counts/pixels)BAT/(total counts/pixels)non-BAT ratio in the right cervical localization showed a significant difference between the groups with higher values in OOB. BMI, PTH, FT4, vitamin D, magnesium, creatinine, and urea had significant correlations with BAT ratios. The predictive values showed that right cervical ratios higher than 1.52 and right supraclavicular ratios lower than 1.15 indicated an increased probability of being OOB. The significant correlations between BAT activation in OOB vs. NO and HPT clinical parameters could be useful for developing potential treatments based on this tissue.
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Drug Discovery Landscape
2 orphan drug designations for Neonatal severe primary hyperparathyroidism, including 1 approved therapy.
2 orphan drug designations for Neonatal severe primary hyperparathyroidism, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
etelcalcetide | small molecules | FDA | Amgen, Inc. | |
paricalcitol [Zemplar] | small molecules | FDA | Approved | Abbvie, inc. |
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