What is Pseudohypoparathyroidism?
Pseudohypoparathyroidism (PHP) is a rare genetic disease where certain body parts don’t react properly to a hormone known as parathyroid hormone (PTH). This hormone helps control the levels of calcium and phosphate in the body. People with PHP experience symptoms similar to another condition known as hypoparathyroidism, which includes low calcium levels and high phosphate levels in the blood. The difference is that though PHP patients also have low calcium and high phosphate levels, they have high, not low, PTH levels in the blood.
PHP is mainly of two types: type 1 and type 2. Type 1 is further categorized into type 1a, 1b, or 1c. The main difference between type 1 and type 2 is the way the body responds to certain protein triggers – in type 1, the response is abnormal, while it’s normal in type 2. When it comes to the subtypes, PHP 1a and 1c can have resistance to multiple hormones, but PHP 1b only affects the kidneys.
Among all the PHP subtypes, type 1a was formerly thought to be the most common, but recent findings show that type 1b occurs with a similar frequency.
What Causes Pseudohypoparathyroidism?
The knowledge on how to diagnose and treat pseudohypoparathyroidism, was first agreed upon by experts from different parts of the world in 2018. Pseudohypoparathyroidism is divided into different groups, known as PHP type 1 and PHP type 2.
In general, PHP type 1 can lead to a decreased response of a chemical messenger called cAMP, and lowered phosphate levels in urine when the body encounters the parathyroid hormone (PTH) – the hormone that regulates our body’s calcium and phosphate levels.
On the other hand, PHP type 2 can lead to normal cAMP reactions, but still results in reduced phosphate levels in the urine when responding to PTH. There are only a handful of PHP type 2 cases, hence we don’t fully understand how it works.
PHP type 1 can be further categorised into a few subtypes, a, b, and c. PHP type 1b typically affects the kidney’s response to PTH, leaving the bone’s PTH response unaffected. It does not have the physical traits seen in Albright hereditary osteodystrophy (AHO) – a condition characterized by short stature, obesity, a round face, short neck, bony growths underneath the skin, and short fingers and toes.
Recent studies are revealing more information about this disease. For example, a mutation in a gene called STX16 has been linked to impulse control resistance in PHP type 1b.
On the other hand, both PHP types 1a and 1c exhibit resistance to PTH and show physical traits associated with AHO. However, PHP type 1a is linked to a reduction of an enzyme called Gs alpha, which results in resistance to many hormones.
PHP type 1c, while similar to 1a due to its multi-hormone resistance, is different as it happens despite normal levels of Gs alpha activity being present.
Risk Factors and Frequency for Pseudohypoparathyroidism
Pseudohypoparathyroidism and Albright hereditary osteodystrophy are very uncommon conditions. They affect between 0.3 and 1.1 people per 100,000 people, and this can vary depending on where you live.
Signs and Symptoms of Pseudohypoparathyroidism
Pseudohypoparathyroidism, or PHP, is typically discovered in young children. This disease might have been passed down from their parents, but it’s not always easy to tell based on family histories. If a child shows signs of the AHO phenotype, then doctors will conduct further biochemical tests.
People with PHP may have symptoms like feeling tingling sensations, numbness around the mouth, and muscle cramps or spasms due to low calcium levels in their blood, also known as hypocalcemia.
When a doctor examines a PHP patient, they may find signs of hypocalcemia. One of the common signs is the Chvostek sign, where tapping on the facial nerve causes facial muscles to contract. Another is the Trousseau sign, which involves inflating a blood pressure cuff to higher than normal levels for three minutes; if the sign is positive, the person will experience hand and foot spasms.
In rare cases, patients might have seizures, and brain imaging may be necessary to check for any issues in the brain. Occasionally, low potassium might also be a sign of PHP.
Types 1a and 1c of PHP may also show signs of hypocalcemia and will display features of the AHO phenotype.
Testing for Pseudohypoparathyroidism
To help diagnose pseudohypoparathyroidism, a disorder that affects calcium and phosphate levels in your body, doctors often check levels of calcium, phosphorus, parathyroid hormone (which controls calcium and phosphate levels), and Vitamin D in your blood. If you have low calcium, high phosphorus, normal Vitamin D, and high parathyroid hormone levels, this may suggest pseudohypoparathyroidism. While a test that uses synthetic PTH (the Ellsworth-Howard test) may help confirm the diagnosis, it is often not necessary.
An electrocardiogram, a test that measures the electrical activity of your heart, may be important to check if you have significantly low calcium levels. This is because low calcium can cause prolonged gaps between heartbeats (a prolonged QT interval) and increase your risk for heart rhythm disturbances (arrhythmias).
If you have pseudohypoparathyroidism, it’s recommended to have your calcium, phosphate, parathyroid hormone, thyroid-stimulating hormone, and the amount of calcium in your urine checked every year. It’s also crucial to monitor your growth and height, and to also test for a growth hormone deficiency, even if your height is normal. Depending on your individual circumstances, you may also need to be screened for other hormonal disorders, such as a deficiency in sex hormones (hypogonadism).
X-rays of your arms and legs may be taken initially to check for short fingers or toes (brachydactyly) or other bone abnormalities.
If you have pseudohypoparathyroidism with a particular set of physical traits known as Albright’s hereditary osteodystrophy, genetic testing is vital. Genetic testing can provide information about possible disease symptoms and future complications. It can also help figure out inheritance patterns, that is, it can provide insight into whether future children may also have pseudohypoparathyroidism.
Treatment Options for Pseudohypoparathyroidism
The main goals in treating pseudohypoparathyroidism (PHP) are keeping calcium and phosphorus levels normal, preventing excessive calcium in the urine (known as hypercalciuria), and if possible, lowering parathyroid hormone (PTH) levels to the normal range. It’s important to note that it’s usually not possible to achieve all of these goals perfectly, but the aim is to get the levels as close to the normal ranges as possible.
In order to keep calcium and phosphorus levels normal, patients may be given calcitriol, a type of vitamin D, which may be combined with calcium supplements. The dosage is adjusted so that the calcium levels remain at the lower end of the normal range. In addition to checking blood calcium levels, it’s also important to keep calcium levels in the urine within the normal range to prevent kidney stones and impaired kidney function.
Patients who persistently have low levels of calcium in their blood, a condition known as hypocalcemia, need to take calcium supplements.
In more acute situations, a patient may need calcium administered directly into the bloodstream (intravenous or IV calcium). This is typically for patients showing symptoms such as spasms or seizures, have abnormal heart rhythm (prolonged QT interval on electrocardiogram), or exceptionally low calcium levels, making their condition high risk. They’ll initially receive a dose of calcium gluconate over a set time period, followed by a slow calcium infusion. As soon as possible, these patients will be switched over to taking calcium and vitamin D orally.
People with PHP will need to take active vitamin D for the rest of their lives, which may be combined with calcium supplements. This type of vitamin D is referred to as calcitriol, as other forms of vitamin D can’t be converted to their active form due to decreased activity of a specific enzyme called 1 alpha-hydroxylase. To maintain calcium levels within the normal range, calcium carbonate or calcium citrate supplements are typically taken.
Alongside this treatment, PTH levels will be closely monitored. The goal is to reduce PTH to within the normal range, or as close as possible, in order to minimize bone loss and the potential development of osteoporosis, a condition that weakens bones and makes them prone to fractures.
Of note, the use of parathyroid hormone or its analogs is not recommended in the treatment of PHP.
What else can Pseudohypoparathyroidism be?
Pseudohypoparathyroidism is a condition that causes low calcium levels, high phosphate levels, high levels of parathyroid hormone (PTH), normal vitamin D levels, and a normal kidney function. Some people with this condition can show signs of Albright hereditary osteodystrophy, but not always. Although no other diseases have exactly the same set of symptoms, some illnesses share similar traits. Here are a few of them:
- True hypoparathyroidism: This condition also leads to low calcium and high phosphate levels, but it comes with low PTH levels. It is typically categorized as either surgical (often caused by parathyroid or thyroid surgery) or non-surgical (which can result from different inherited or acquired disorders such as hemochromatosis, gene mutations, or autoimmune polyendocrine syndrome type 1).
- Vitamin D deficiency: This condition leads to low calcium and high PTH levels. The level of 25 OH vitamin D, a form of vitamin D, is obviously low.
- Worsening chronic kidney disease (CKD): Patients with a lower glomerular filtration rate show similar findings. Kidney function decline often leads to low levels of active vitamin D due to impaired conversion and high phosphate levels due to declining filtration. This situation induces the release of more PTH.
What to expect with Pseudohypoparathyroidism
The outlook for patients with PHP (Pseudohypoparathyroidism) can vary. If you have a mild version of the condition and it is managed well with calcium and vitamin D supplements, it’s likely you can expect to live a normal length of life. However, for individuals with severe cases that include features of AHO (Albright hereditary osteodystrophy), which can involve obesity, sleep apnea, and learning disabilities, the disease can significantly affect quality of life and potentially reduce life expectancy.
Possible Complications When Diagnosed with Pseudohypoparathyroidism
Long-term low calcium and high phosphorus in the blood can sometimes lead to a condition similar to Parkinson’s disease. This condition may or may not improve with the right amount of calcium and vitamin D supplements.
Children who have short fingers may struggle with tasks that require detailed hand movements.
Carpal tunnel syndrome, a condition where a nerve in the wrist gets compressed, is more commonly found in patients with a condition called Albright’s hereditary osteodystrophy.
There have been increased cases and early occurrence of spinal stenosis, a narrowing of the spaces in the spine which can cause weakness in the lower body.
Lastly, the risk for sleep apnea, a serious sleep disorder where breathing repeatedly stops and starts, is more than four times higher than normal in children.
The above conditions:
- Low calcium and high phosphorous results in Parkinson’s-like condition
- Children with short fingers struggle with detailed hand movements
- Increased cases of carpal tunnel syndrome in Albright’s hereditary osteodystrophy patients
- More and early occurrence of spinal stenosis causing weakness in lower body
- Over four times increased risk for sleep apnea in children
Preventing Pseudohypoparathyroidism
Pseudohypoparathyroidism (PHP) is a disease that one can inherit or receive from their parents’ genes. Unfortunately, once a person has PHP, it can’t be cured. Genetic testing and counseling are usually suggested for people with this condition. This advice is particularly important if they plan to have children, as it can give them a clear idea of the likelihood of their child inheriting the disease.
Even if people with PHP feel healthy, it’s suggested that they have yearly check-ups. This is to ensure their condition is managed properly and to identify any possible complications at an early stage.