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Neonatal severe hyperparathyroidism
This serious condition affects newborns and is caused by genetic changes that disrupt the body's ability to regulate calcium. It requires prompt diagnosis and specialist medical care to manage the potentially life-threatening symptoms.
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Overview
Neonatal severe hyperparathyroidism (NSHPT) is a very rare inherited disorder that causes dangerously high levels of calcium in a baby's blood, a condition known as hypercalcaemia [PMID:33678033]. This high calcium level is due to overactivity of the parathyroid glands, four small glands located in the neck near the thyroid gland. These glands normally produce parathyroid hormone (PTH), which helps regulate calcium. In NSHPT, the parathyroid glands are overactive and release too much PTH, leading to excessive calcium in the bloodstream.
Symptoms typically appear shortly after birth, often within the first few days or weeks of life. Early recognition and treatment are crucial because persistent high calcium levels can lead to serious health complications affecting multiple body systems.
Symptoms & clinical features
Newborns with NSHPT can exhibit a range of symptoms, primarily related to the very high levels of calcium in their blood. These may include poor feeding, vomiting, and constipation [PMID:33678033]. Affected infants might also appear generally unwell, with symptoms such as lethargy, floppiness (hypotonia), and muscle weakness.
High calcium levels can also impact bone health, leading to poorly mineralised bones, which can increase the risk of bone fractures. Additionally, babies with NSHPT may experience breathing difficulties and a lack of weight gain. In severe cases, untreated hypercalcaemia can be life-threatening.
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Affected organs
The primary organ system affected in NSHPT is the endocrine system, specifically the parathyroid glands, which become enlarged and overactive. This overactivity then impacts calcium regulation throughout the body.
The skeletal system is significantly affected, with bones becoming less dense and more prone to fractures due to abnormal calcium and phosphate metabolism. The kidneys can also be affected by high calcium levels, potentially leading to dehydration and impaired kidney function. Other systems, including the digestive system (leading to feeding issues) and the nervous system (causing lethargy and floppiness), may also show signs of impact due to the systemic effects of hypercalcaemia.
Risks & severity
Neonatal severe hyperparathyroidism is a serious condition with significant potential for severe health complications if not promptly diagnosed and managed. The severity of symptoms can vary but is often profound due to extremely high calcium levels shortly after birth. Without intervention, sustained hypercalcaemia can lead to life-threatening issues, including severe dehydration, kidney problems, and profound muscle weakness affecting breathing.
The long-term outlook for individuals with NSHPT depends heavily on early diagnosis and effective treatment. With appropriate medical management, many individuals can achieve better health outcomes. However, some may experience ongoing issues related to bone health or kidney function.
Genetic causes
Neonatal severe hyperparathyroidism is typically caused by genetic changes (pathogenic variants) in the CASR gene [PMID:31557088]. The CASR gene provides instructions for making the calcium-sensing receptor (CaSR) protein. This protein is found primarily on the surface of cells in the parathyroid glands and kidneys.
The CaSR protein acts like a 'calcium sensor'. Its normal function is to monitor blood calcium levels and signal to the parathyroid glands when these levels are too low or too high. If calcium levels are low, the CaSR signals for more parathyroid hormone (PTH) to be released; if calcium levels are high, it signals to reduce PTH release. Pathogenic variants in CASR can cause the receptor to be much less sensitive to calcium, meaning the parathyroid glands continue to release excessive PTH even when blood calcium levels are already very high [PMID:31557088]. This leads to the characteristic hypercalcaemia seen in NSHPT.
- CASR calcium sensing receptorThe CASR gene encodes the calcium-sensing receptor, a protein crucial for monitoring and regulating calcium levels in the blood and maintaining mineral homeostasis.
Inheritance pattern
Neonatal severe hyperparathyroidism is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the changed CASR gene - one from each parent - to develop the condition.
Parents who each carry one copy of a pathogenic CASR variant are typically healthy and do not show symptoms of NSHPT; they are referred to as carriers. When two carriers have a child, there is a 25% chance with each pregnancy that the child will inherit two copies of the changed gene and develop NSHPT. There is also a 50% chance the child will be a carrier like their parents, and a 25% chance the child will inherit two normal copies of the gene.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of neonatal severe hyperparathyroidism is usually suspected based on a newborn's clinical symptoms and very high blood calcium levels. Blood tests will typically show significantly elevated calcium and parathyroid hormone (PTH) levels. Once NSHPT is suspected, genetic testing is used to confirm the diagnosis by identifying pathogenic variants in the CASR gene [PMID:33678033].
In the UK, genetic testing for NSHPT would typically be requested by a specialist paediatrician or endocrinologist. Referrals for genetic testing are often made via Clinical Genetics services. The NHS Genomic Medicine Service (GMS) provides a national testing service, and testing for conditions like NSHPT falls under specific R-codes for rare inherited diseases. A genetic counsellor can provide support and information throughout the diagnostic process.
Management & lifestyle
Management of neonatal severe hyperparathyroidism focuses on rapidly and effectively lowering dangerously high calcium levels and preventing complications. Initial treatment often involves intravenous fluids to help excrete calcium, and medications such as calcitonin or bisphosphonates may be used to reduce blood calcium levels. In some severe cases, surgical removal of the parathyroid glands (parathyroidectomy) may be considered, especially if medical treatments are not sufficient to control hypercalcaemia [PMID:33678033].
Care for individuals with NSHPT is typically provided by a multidisciplinary team, including paediatric endocrinologists, surgeons, and geneticists. Ongoing monitoring of calcium levels and bone health is essential. Genetic counselling is also an important part of care, offering information about the condition, its inheritance, and support for families.
UK care pathway
In the UK, if neonatal severe hyperparathyroidism is suspected, your baby will likely be referred to a specialist paediatrician or endocrinologist. Diagnosis is confirmed through genetic testing, which is available through the NHS Genomic Medicine Service. Referrals for genetic testing are often made through a local Clinical Genetics service.
Genetic counsellors are an integral part of this pathway, providing essential information and support to families regarding the genetic diagnosis, inheritance patterns, and implications for family planning. The relevant testing for this condition would fall under an NHS R-code, facilitating access to diagnostic services.
Frequently asked questions
What is the difference between neonatal severe hyperparathyroidism and familial hypocalciuric hypercalcaemia?
Both conditions can be caused by changes in the CASR gene. However, neonatal severe hyperparathyroidism is a very severe form that presents in newborns with dangerously high calcium levels, whereas familial hypocalciuric hypercalcaemia is typically a much milder condition, often with no symptoms, and does not usually require treatment.
How is NSHPT inherited?
NSHPT is inherited in an autosomal recessive manner. This means a child must inherit two changed copies of the CASR gene, one from each parent, to develop the condition. Parents who each carry one changed copy are usually healthy carriers.
Can NSHPT be treated?
Yes, NSHPT can be treated. Management focuses on lowering high calcium levels quickly, often using medications and sometimes requiring surgery to remove the overactive parathyroid glands. Early and effective treatment is crucial for better outcomes.
What kind of doctors treat NSHPT?
Children with NSHPT are typically cared for by a team of specialists. This often includes paediatric endocrinologists (hormone specialists), surgeons, and geneticists. A genetic counsellor will also provide support and information to the family.
Are there long-term health effects of NSHPT?
With prompt and effective treatment, many of the immediate dangers of NSHPT can be managed. However, some individuals may experience ongoing challenges related to bone health or kidney function, requiring continued monitoring and care.
References
- Minisola S, Arnold A, Belaya Z. Epidemiology, Pathophysiology, and Genetics of Primary Hyperparathyroidism. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2022. PMID: 36245271
- Jamshidi R, Egan JC. Pediatric parathyroid disease. Seminars in pediatric surgery. 2020. PMID: 32571508
- Masi L. Primary Hyperparathyroidism. Frontiers of hormone research. 2019. PMID: 30641515
- Vannucci L, Brandi ML. Familial Hypocalciuric Hypercalcemia and Neonatal Severe Hyperparathyroidism. Frontiers of hormone research. 2019. PMID: 30641521
- Alshanafey S, Maqbol S, AlAmeer A. Surgical management of neonatal severe hyperparathyroidism. Annals of Saudi medicine. 2023. PMID: 37916585
- Khalatbari H, Cheeney SHE, Manning SC. Pediatric hyperparathyroidism: review and imaging update. Pediatric radiology. 2021. PMID: 33904951
- Marx SJ, Sinaii N. Neonatal Severe Hyperparathyroidism: Novel Insights From Calcium, PTH, and the CASR Gene. The Journal of clinical endocrinology and metabolism. 2020. PMID: 31778168
- Gorvin CM. Genetic causes of neonatal and infantile hypercalcaemia. Pediatric nephrology (Berlin, Germany). 2022. PMID: 33990852